KR100221370B1 - Composition for promoting wound-healing containing 15-keto-prostaglandin - Google Patents

Abstract

A use of a 15-keto-prostaglandin compound for the manufacture of a medicament for promoting healing of wound.

Description

Pharmaceutical compositions for promoting the treatment of wounds

The present invention relates to methods of promoting wound-treatment using 15-ketoprostaglandin compounds.

Prostaglandins (hereafter prostaglandins are referred to as PGs) are members of the class of organic carboxylic acids contained in humans and most other mammalian tissues or organs and exhibit a wide range of physiological activities. Natural PG has a common structural feature with prostanoic acid backbone of formula (A).

[Formula 1]

Some synthetic analogs have a somewhat modified backbone.

Primary PGs are classified as PGA, PGB, PGC, PGD, PGE, PGF, PGG, PGH, PGI and PGJ based on the structural features of the five-membered ring residues, and also 13, 14-unsaturated-15-OH (subclass 1) , 5, 6- and 13, 14-unsaturated-15-OH (subclass 2), and 5, 6-, 13, 14- and 17, 18-triunsaturated-15-OH (subclass 3) In the above formula (A), the group is classified based on the presence or absence of an unsaturated group or an oxidizing group in the chain residue.

PGF also depends on the coordination of hydroxy groups at position 9 (Hydroxy group In coordination) and (Hydroxy group In coordination).

Natural PGE ₁ is known to have wound-healing promoting activity.

In addition, natural PGE ₁ α, PGE ₂ α and PGE ₃ α are known to have vasodilation, hypotension, decreased gastric secretion, hyperintestinal-motility, uterine contraction, diuresis, bronchiectasis and ulcer-therapeutic activity.

In addition, PGF ₁ , PGF ₂ and PGF ₃ are known to have hypertension, vasoconstriction, intestinal-motility, uterine contraction, luteal-degeneration and bronchial contractile activity.

In addition, some 15-ketos (ie, having an oxo group instead of a hydroxy group at position 15) and prostaglandins and 13,14-dihydro-15-ketoprostaglandins are substances that are naturally produced by enzymatic action upon metabolism of primary PG. Known as [Acta Physiologica Scandinavica, 66, 509, 1966].

The document also discloses that 15-ketoprostaglandin F ₂ α has a pregnancy suppression activity.

EP 0,310,305 discloses that 15-keto-PG can be used as a laxative.

However, this document does not record whether the 15-ketoprostaglandin compound has a therapeutic effect on promoting wound-treatment.

An extensive study of the biological properties of 15-ketoprostaglandin compounds has shown that the compounds are useful as medicaments for promoting wound healing.

In a first aspect, the present invention provides a method for facilitating the treatment of a wound, comprising administering to the patient in need thereof a therapeutically effective amount of a 15-ketoprostaglandin compound.

In a second aspect, the present invention provides the use of a 15-ketoprostaglandin compound in the manufacture of a medicament for promoting the treatment of a wound.

In a third aspect, the present invention provides a pharmaceutical composition for promoting the treatment of a wound, comprising a 15-ketoprostaglandin compound with a pharmaceutically acceptable carrier, diluent or excipient.

The term "wound" refers to a condition in which tissue is separated or cut by external (eg, mechanical, chemical, physical, etc.) action.

In a typical upper body, a portion of tissue that is not exposed to air under normal conditions is exposed to air.

Wounds include surgical wounds, accidental damages, and intentional damages.

Wounds can occur anywhere in the body.

In one embodiment, the wound includes a wound or damage to the cornea.

Corneal wounds or injuries may be caused by surgery, trauma or physical wounds, bacterial or viral infections of the cornea, decreased tear secretion, corneal dystrophy, ultraviolet irradiation, etc. Irrespective of wounds and injuries of all corneas.

Surgical wounds include perforation of the cornea, corneal epithelial debridement, corneal resection (eg, to remove corneal protrusion or corneal plaque), lens aspiration incision, iris dissection, and the like.

The term “treatment” or “treating” as used herein inhibits a disease in a mammal, including preventing a disease, treating a disease, alleviating a disease, inhibiting or alleviating the development of the disease. Says any way.

The term "15-ketoprostaglandin compound", referred to as a 15-keto-PG compound, refers to an oxo instead of a hydroxy group at position 15 of the prostinoic acid nucleus, regardless of the presence or absence of a double bond between positions 13 and 14. Any prostaglandin derivative having a group.

[nomenclature]

The instruction of the 15-keto-PG compound herein uses the prostinoic acid number system represented by the above structural formula (A).

Although structural formula (A) shows a basic skeleton having 20 carbon atoms, the 15-keto-PG compounds used in the present invention are not limited to those having the same number of carbon atoms. Adjacent to carboxylic acid carbon atoms -Starting with carbon atoms -The numbers 2-7 attached to the 5-membered ring in the chain Chains are numbered 8-12, starting from the carbon atom to which they are attached, starting from the carbon atom adjacent to the ring. -Numbers 13 to 20 are attached to the chain. The number of carbon atoms When decremented in a chain, numbers are deleted in sequence starting at position 2, and the number of carbon atoms When increased in the chain, the compounds are named as substituted derivatives having respective substituents at position 1 instead of carboxy group (C-1). Similarly, the number of carbon atoms If reduced in the chain, the numbers are deleted one after the other, starting at position 20. When increased in the chain, the compounds are named as substituted derivatives having respective substituents at position 20. The stereochemistry of the compound is the same as in formula (A) above unless otherwise specified. therefore, The 15-keto-PG compound having 10 carbon atoms in the chain is ordered as 15-keto-20-ethyl-PG.

Since the above structural formulas represent the most typical specific configuration, the compounds having the configuration are represented herein without specific reference thereto.

In general, PGD, PGE and PGF have a hydroxy group on the carbon atom at positions 9 and / or 11, but herein the term “15-keto-PG compound” is hydrated at positions 9 and / or 11 PGs with groups other than the siloxane group. Such PGs are referred to as 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted -PG compounds.

As mentioned above, the nomenclature of 15-keto-PG compounds is based on prostanoic acid. However, such compounds may also be named according to the IUPAC nomenclature. For example, 13, 14-dihydro-15-keto-16R, S-fluoro-PGE ₂ is (Z) -7-{(1R, 2R, 3R) -3-hydroxy-2-[(4R , S) -4-fluoro-3-oxo-1-octyl] -5-oxocyclopentyl} -hept-5-enoic acid. 13,14-Dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE ₂ methyl ester is 7-{(1R, 2S, 3S) -3-methyl-2- [3- Oxo-1-decyl] -5-oxocyclopentyl} -hept-5-enoate. 13, 14-dihydro-6, 15-diketo-19-methyl-PGE ₂ ethyl ester is ethyl 7-{(1R, 2S, 3S) -3-hydroxy-2- (7-methyl-3-oxo -1-octyl) -5-oxo-cyclopentyl} -6-oxo-heptanoate. 13, 14-dihydro-15-keto-20-ethyl-PGF _2α isopropyl ester isopropyl (Z) -7-[(1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- {3-oxo-1-decyl} -cyclopentyl] -hept-5-enoate. 13,14-dihydro-15-keto-20-methyl-PGF _2α methyl ester is methyl (Z) -7-[(1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- {3 -Oxo-1-nonyl} -cyclopentyl] -hept-5-enoate.

The 15-keto-PG compounds used in the present invention may be any derivative of PG as long as they have an oxo group at position 15 instead of a hydroxy group, and one double bond between positions 13 and 14 (subclass 1). 15-keto-PG compound), two double bonds between positions 13 and 14 as well as positions 5 and 6 (15-keto-PG compounds of subclass 2), or positions 13 and 14, positions 5 and 6 Position as well as three double bonds (15-keto-PG compounds of subclass 3) between positions 17 and 18, and one single bond (13, 14-dihydro-15) between positions 13 and 14 -Keto-PG compound).

Typical examples of compounds used in the present invention include 15-keto-PG (subclass 1), 15-keto-PG (subclass 2), 15-keto-PG (subclass 3), 13, 14, wherein the PGs are as defined above. -Dihydro-15-keto-PG (subclass 1), 13, 14-dihydro-15-keto-PG (subclass 2), and 13, 14-dihydro-15-keto-PG (subclass 3) as well Derivatives thereof.

Examples of substituted products or derivatives include Esters in the carboxyl group of the chain, pharmaceutically or physiologically acceptable salts, unsaturated derivatives having double or triple bonds between positions 2 and 3 or positions 5 and 6, respectively, 3, 5, 6, 16, Substituted derivatives having substituent (s) on the carbon atom (s) at positions 17, 19 and / or 20, and lower alkyl or hydroxy (lower) at positions 9 and / or 11 instead of hydroxy groups of said PG; The compound which has an alkyl group is mentioned.

Examples of substituents present in the preferred compounds are as follows: Substituents on the carbon atom at positions 3, 17 and / or 19 include lower alkyl, for example C ₁ to C ₄ alkyl, in particular methyl and ethyl. Substituents on the carbon atom at position 16 include lower alkyl (e.g. methyl, ethyl, etc.), hydroxy and halogen atoms (e.g. chlorine, fluorine), aryloxy (e.g. trifluoromethylphenoxy ), And the like. Substituents on the carbon atom at position 17 include halogen atoms such as chlorine and fluorine. Substituents on the carbon atom at position 20 include, but are not limited to, saturated and unsaturated lower alkyls such as C ₁ to C ₄ alkyl, lower alkoxy, such as C ₁ to C ₄ alkoxy, and lower alkoxy (lower) alkyl, such as C ₁ to C ₄ alkoxy-C ₁ to C ₄ alkyl are mentioned. Examples of the substituent on the carbon atom at position 5 include a halogen atom such as chlorine and fluorine. Substituents on the carbon atom at the 6-position include an oxo group forming carbonyl. The stereochemistry of PG with hydroxy, lower alkyl or lower (hydroxy) alkyl substituents on carbon atoms at positions 9 and / or 11 is , Or a mixture thereof.

The derivative has a chain shorter than the primary PG It may also have an alkoxy, phenoxy or phenyl group at the end of the chain.

In particular, preferred compounds are compounds having lower alkyl (e.g. methyl, ethyl, etc.), halogen atoms (e.g. chloro, fluorine, etc.) at position 16, halogen atoms (e.g. chloro , Compounds having lower alkyl (eg methyl, ethyl, etc.) at position 19, compounds having halogen atoms (eg chloro, fluorine, etc.) at position 5, 6 A compound having an oxo group at position 20, a compound having lower alkyl (eg methyl, ethyl, etc.) at position 20 and phenyl optionally substituted with halogen or haloalkyl at position 16 instead of the remaining position of the alkyl chain, or It is a compound having phenoxy.

Preferred compound groups used in the present invention have the following general formula (1).

Wherein X and Y are hydrogen, hydroxy, halo, lower alkyl, hydroxy (lower) alkyl or oxo, provided that at least one of X and Y is a group other than hydrogen and the five-membered ring is at least one double May have a bond, Z is hydrogen or halo, A is -CH ₂ OH, -COCH ₂ OH, -COOH or a functional derivative thereof, and B is -CH ₂ -CH ₂ , -CH = CH- or- C = C-, R ₁ is a divalent saturated or unsaturated lower or intermediate aliphatic hydrocarbon residue, unsubstituted or substituted with halo, oxo or aryl, and R ₂ is unsubstituted, or halo, hydroxy, oxo , Saturated or unsaturated lower or intermediate aliphatic hydrocarbon residues substituted with lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, aryl or aryloxy.

Among the compounds of the general formula, a compound represented by the following general formula (2) or a pharmaceutically acceptable salt thereof (Ra is hydrogen) is preferable.

Wherein O ₁ is halogen, O ₂ is hydrogen or halogen, E is —CH ₂ —CH ₂ — or —CH═CH—, Ra is hydrogen or lower alkyl, and Rb is a single race or lower alkylene Rc is lower alkyl unsubstituted or substituted with halogen, lower cycloalkyl unsubstituted or substituted with lower alkyl, monocyclic aryl unsubstituted or substituted with halogen or halo (lower) alkyl or halogen or halo Monocyclic aryloxy substituted with (lower) alkyl.

Moreover, among the compounds of the said general formula, the compound represented by following General formula (3) or its pharmaceutically acceptable salt (R <_1> is a hydrogen atom) is preferable.

Wherein L and M are hydrogen atoms, hydroxy, lower alkyl, hydroxy (lower) alkyl or oxo, provided that at least one of L and M is not a hydrogen atom, and the 5-membered ring is 1 or 2 double bonds And O ₁ ′ and O ₂ ′ are hydrogen atoms, halogen atoms or lower alkyl, and D is —CH ₂ —CH ₂ —, —CH═CH—, —C≡C— or —CO—CH ₂ -, E is -CH ₂ -CH ₂ -or -CH = CH-, W is -CH ₂ -CH ₂ -CH _2- , -CH = CH-CH ₂ or CH ₂ -CH = CH-, Ra 'is hydrogen atom, lower alkyl, cyclo (lower) alkyl, monocyclic aryl, monocyclic aryl (lower) alkyl or monocyclic aroyl (lower) alkyl, Rb' is single bond or lower alkylene Rc 'is lower alkyl unsubstituted or substituted with halogen, lower cycloalkyl unsubstituted or substituted with lower alkyl, monocyclic aryl unsubstituted or substituted with halogen or halo (lower) alkyl, or Monocyclic aryloxy unsubstituted or substituted with halogen or halo (lower) alkyl.

In the above general formula, the term “unsaturated” as defined in R ₁ and R ₂ is one or more, and optionally more than one, double, and / or triple bonds present between the carbon atoms of the main and / or side chains, separately, individually It means to include as or continuously. According to the universal nomenclature, the unsaturated group between two consecutive positions is represented by indicating the low number between two positions in between, and the unsaturated group between two terminal positions is indicated by indicating all of the positions. Preferred unsaturated groups are double bonds in position 2 and double or triple bonds in position 5.

"Lower or intermediate aliphatic hydrocarbon residue" means a straight or branched chain hydrocarbon group having 1 to 4 carbon atoms, preferably 2 to 8 carbon atoms for R ₁ and 2 to 10 carbon atoms for R ₂ It refers to a straight or branched chain hydrocarbon group having (for example, it is preferable to have 1 to 3 carbon atoms for the side chain).

"Halo" refers to fluoro, chloro, bromo and iodine.

"Lower" refers to a group having from 1 to 6 carbon atoms unless otherwise specified.

"Lower alkyl" as a group or moiety in hydroxy (lower) alkyl means a saturated straight or branched chain hydrocarbon radical having 1 to 6, preferably 1 to 5, more preferably 1 to 4 carbon atoms, For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

"Lower alkoxy" refers to lower-alkyl-0-groups wherein lower alkyl is as defined above.

"Lower alkylene" refers to a group obtainable by removing a hydrogen atom from a lower alkyl group as defined above, such as methylene, ethylene, propylene, tetramethylene, 2-methyl tetramethylene, pentamethylene, hexamethylene and the like. Say

"Halo (lower) alkyl" means a lower alkyl group as defined above substituted with one or more, preferably 1 to 3 halogen atoms as defined above, for example chloromethyl, bromomethyl, fluoromethyl , Trifluoromethyl, 1, 2-dichloromethyl, 1, 2, 2-trichloromethyl, chloropropyl, chlorobutyl, chloropentyl, chlorohexyl and the like.

By "hydroxy (lower) alkyl" is alkyl as defined above substituted with one or more hydroxy groups, for example hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxy Oxyethyl.

"Lower alkanoyloxy" refers to a group of the general formula RCO-O-, wherein RCO- is an acyl group formed by oxidation of a lower alkyl group as defined above, for example acetyl.

"Cyclo (lower) alkyl" refers to a cyclic group formed by cyclization of a lower alkyl group as defined above.

"Aryl" means an unsubstituted or substituted aromatic carbocyclic or heterocyclic (preferably monocyclic) group such as phenyl, tolyl, xylyl and thienyl. Examples of substituents are halo and halo (lower) alkyl as defined above.

"Aryloxy" refers to a group of the general formula ArO-, wherein Ar is aryl as defined above.

"Monocyclic aryl" refers to phenyl unsubstituted or substituted with lower alkyl substituents such as phenyl, tolyl, xylyl, cumenyl and the like.

"Monocyclic aryloxy" refers to a group of the general formula mArO-, where mAr is monocyclic aryl as defined above, such as phenoxy, tolyloxy, cumenyloxy and the like.

"Monocyclic aryl (lower) alkyl" refers to a group consisting of a monocyclic aryl and a lower alkyl bonded together as defined above, for example, benzyl, phenethyl, tolylmethyl and the like.

"Monocyclic aroyl (lower) alkyl" refers to a group consisting of monocyclic aroyl, such as benzoyl, unsubstituted or substituted with lower alkyl substituents, and lower alkyl as defined above, bonded together, eg For example, phenacyl (benzoyl) methyl, toluoylmethyl, xyloylmethyl, etc. are mentioned.

Carboxylic "functional derivatives" as A include salts (preferably pharmaceutically acceptable salts), esters and amides.

Suitable “pharmaceutically acceptable salts” include conventional non-toxic salts and include salts with inorganic bases such as alkali metal salts (eg sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg calcium salts, magnesium Salts), ammonium salts; Salts with organic bases, such as amine salts (e.g., methylamine salts, dimethylamine salts, cyclohexylamine salts, benzylamine salts, piperidine salts, ethylenediamine salts, ethanolamine salts, diethanolamine salts, triethanolamine Salts, tris (hydroxymethylamino) ethane salts, monomethylmonoethanolamine salts, procaine salts, caffeine salts and the like), basic amino acid lead (eg arginine salts, lysine salts, etc.), tetraalkyl ammonium salts and the like. Such salts can be prepared, for example, from the corresponding acids and bases by conventional methods or by salt exchange.

Examples of esters are aliphatic esters such as C _1-6 alkyl esters (eg, methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-esters, 1-cyclopropyl Esters), lower alkenyl esters (e.g. vinyl esters, allyl esters, etc.), lower alkynyls (e.g. ethynyl esters, propynyl esters, etc.), hydroxy (lower) alkyl esters ( For example, hydroxyethyl ester), lower alkoxy (lower) -alkyl ester (for example, methoxymethyl ester, 1-methoxyethyl ester, etc.); And aromatic esters such as optionally substituted aryl esters (eg phenyl esters, tolyl esters, t-butyl phenyl esters, salicylic esters, 3, 4-di-methoxyphenyl esters, benz amido phenyl esters) And the like, and aryl (lower) alkyl esters (e.g., benzyl esters, trityl esters, benzhydryl esters, etc.). Examples of amides are mono- or di-lower alkyl amides (eg methylamide, ethylamide, dimethylamide, etc.), arylamides (eg anilide, toluidide), and lower alkyl- or aryl-sulls Phonylamide (eg, methylsulfonylamide, ethylsulfonylamide, tolylsulfonylamide, and the like).

Preferred examples of A include -COOH, COOCH ₃ , -COOCH ₂ CH ₃ , -COOCH (CH ₃ ) ₂ and -CONHSO ₂ CH ₃ .

Examples of preferred R ₁ include-(CH ₂ ) ₂ -,-(CH ₂ ) _6- , -CH ₂ CO (CH ₂ ) _2- , -CH ₂ CH = CH (CH ₂ ) _3- , -CH ₂ CO (CH ₂ ) ₄ -,-(CH ₂ ) CH = CH (CH ₂ ) ₂ -,-(CH ₂ ) ₄ CH = CH-, -CH ₂ CH = C = CH (CH ₂ ) ₂ -and the like. Can be mentioned.

Examples of preferred R ₂ include — (CH ₂ ) ₂ CO (CH ₂ ) ₄ —CH ₃ , — (CH ₂ ) ₂ CO (CH ₂ ) ₄ —COOH, — (CH ₂ ) ₂ COC (CH ₃ ) ₂ (CH ₂ ) ₃ -CH ₃ ,-(CH ₂ ) ₂ COCH ₂ O-phenyl,-(CH ₂ ) ₂ COCH ₂ O-methchlorophenyl,-(CH ₂ ) ₂ COCH ₂ O-metatrifluorophenyl ,-(CH ₂ ) ₂ COCH ₂ O-3-thienyl,-(CH ₂ ) ₂ CO (CH ₂ ) ₂ -phenyl,-(CH ₂ ) ₂ COCH ₂ CH (CH ₃ ) (CH ₂ ) CH ₃ ,-(CH ₂ ) ₂ COC (CH ₃ ) ₂ CH ₂ OCH ₂ CH ₃ ,-(CH ₂ ) ₂ COCH (CH = CH) (CH ₂ ) ₃ CH ₃ ,-(CH ₂ ) ₂ CO-cyclopentyl ,-(CH ₂ ) ₂ CO-cyclohexyl,-(CH ₂ ) ₂ CO (CH ₂ ) ₂ -cyclohexyl,-(CH ₂ ) ₂ COCH ₂ CH (CH ₃ ) (CH ₂ ) CH = C- ( CH ₃ ) ₂ ,-(CH ₂ ) ₂ COCH (CH ₃ ) CH ₂ CC≡CH, -CH = CHCO (CH ₂ ) ₄ -CH ₃ , -CH = CHCOC (CH ₃ ) ₂ (CH ₂ ) _3- CH _3, -CH = CHCOCH ₂ O- phenyl, -CH = CHCOCH ₂ O- meta-chlorophenyl, -CH = CHCOCH ₂ O- in the meta-trifluoromethyl-phenyl, -CH = CHCOCH ₂ O-3- thienyl, -CH = CHCO (CH ₂ ) ₂ -phenyl, -CH-CHCOCH ₂ CH (CH ₃ ) (CH 2) ₃ CH ₃ , -CH = CHCOC (CH ₃ ) ₂ CH ₂ OCH ₂ CH ₃ , -CH = CHCOCH ( _{CH = CH) (CH 2)} 3 CH 3, -CH = CHCO- cycle Cyclopentyl, -CH = CHCO- _{cyclohexyl, -CH = CHCOCCH 2 CH (CH} 3) (CH 2) 2 CH = C (CH 3) 2, -CH = CHCOH (CH 3) CH 2 CC = CH, -CH = CHCOCH (CH ₃ ) (CH ₂ ) ₄ CH _{3 And} the like.

Ring and in the general formula (1) and (2) And / or The coordination of the chains may be the same as or different from the coordination with natural prostaglandins. However, the present invention also encompasses mixtures of compounds with natural coordination and compounds with non-natural coordination.

Examples of typical compounds of the invention include 15-keto-PG and 13, 14-dihydro-15-keto-PG, and derivatives thereof such as 6-oxo-derivatives, Δ ² -derivatives, 3R, S- Methyl-derivatives, 5R, S-fluoro-derivatives, 5, 5-difluoro-derivatives, 16R, S-methyl-derivatives, 16, 16-dimethyl-derivatives, 16R, S-fluoro-derivatives, 16, 16 -Difluoro-derivatives, 17S-methyl-derivatives, 17R, S-fluoro-derivatives, 17, 17-difluoro-derivatives, 19-methyl-derivatives, 20-methyl-derivatives, 20-ethyl-derivatives, 19 -Desmethyl-derivatives, 16-desbutyl-16-phenoxy-derivatives and 2-decarboxy-2-carboxyalkyl derivatives.

In the 15-keto-PG compound used in the present invention, when the bond between 13-position and 14-position is saturated, sometimes hemiacetal between the hydroxy group at position 11 and the keto group at position 15 Keto-hemiacetal equilibrium can be achieved by forming

When tautomers are present, the proportion of isomers present varies depending on the structure of the other part of the molecule or the type of possible substituents, and sometimes one isomer may prevail over other isomers. However, the present invention includes both isomers. While any compound of the present invention may be represented by a structure or nomenclature based on keto-forms, it is to be understood that this structure or nomenclature is merely for convenience and is not intended to exclude hemiacetal type isomeric compounds.

In the present invention, individual tautomers, mixtures thereof, or other isomers such as optical isomers, mixtures thereof, racemic mixtures, and stereoisomers may be used for some purposes.

Some of the compounds used in the present invention are novel and are disclosed in Japanese Patent Application Laid-Open Nos. 64-52753, No. 1-104040, No. 1-151519, No. 2-131446 No. (Pyeong) 3-29310. Such compounds may also be prepared by methods analogous to those described in the publications above or by known methods.

Practical methods for preparing 15-keto compounds include the following steps:

Referring to the following synthetic schemes (1) to (3), aldehyde (2) prepared by oxidizing a commercially available (-)-corey lactone (1) to Collins (Collins) dimethyl (2-oxo) Heptyl) phosphate anion , Unsaturated ketone (3) is prepared and , -Unsaturated ketones are reduced with the corresponding saturated ketones (4), the carbonyl groups of the ketones (4) are protected with the corresponding ketals (5) using diols and deprotected with p-phenylbenzoyl groups The corresponding alcohol (6) is prepared, followed by protecting the longitudinally derived hydroxy group with dihydropyran to produce the corresponding tetrahydropyranyl ether (7). According to the above process, A precursor of PGE whose chain is 13, 14-dihydro-15-keto-alkyl group is prepared.

Using the tetrahydropyranyl ether (7), a group consisting of carbon atoms at positions 5, 6 and 7 -Phosine 6-keto-PGE ₁ (15) can be prepared as follows:

Tetrahydro pyranyl ether (7) was reduced using diisobutyl aluminum hydride to prepare the corresponding lactol (8), which was prepared from (4-carboxybutyl) triphenylphosphonium bromide Reacted with the iridate, followed by esterification (10), and cyclization between 5, 6-double bond and C-9 hydroxyl group using NBS or iodine to give halogenated compound (11), Dehalogenation of 11), for example, with DBU, affords 6-keto compound (13), and oxidizes it with Jones to remove the protecting group to produce the target compound.

In addition, the groups consisting of carbon atoms at positions 5, 6 and 7 Phosphorus PGE ₂ 19 can be prepared as follows:

As shown in the synthesis diagram ((II), the tetrahydropyranyl ether (7) was reduced to give lactol (8), and the resulting lactol (8) was obtained from (4-carboxybutyl) triphenylphosphonium bromide. Reaction with the resulting illide yields a carboxylic acid (16) which is then esterified to yield ester (17), and the obtained ester (17) is oxidized to yield compound (18), followed by removal of the protecting group The target compound is removed.

Compound having a group of -CH ₂ CH 5 = 5 of the compound (18) produced using the tetrahydropyranyl ether (7) as a starting material using the same preparation method as PGE ₂ having a group of -CH ₂ CH = CH- It can be prepared by catalytic reduction of the double bond between position 6 and the removal of the protecting group.

constitutional formula 5, 6-dehydro-PGE ₂ having the general formula or Copper enolate formed by 1,4-addition reaction of monoalkyl copper complex or dialkyl copper complex of G wherein alkyl is 4R-t-butyldimethylsilyloxy-2-cyclopenten-l-one with 6 -Alkoxycarbonyl-1-iodo-2-hexine or its derivatives can be synthesized.

11- Type PGE can be prepared according to the following synthetic scheme (3).

PGE derivatives having methyl groups instead of hydroxy at the 11-position can be prepared by reacting PGA type compounds obtained by Jones oxidation of 9-hydroxy-11-tosylate with dimethyl copper complexes. Alternatively, such compounds protect the carbonyl groups of saturated ketones (4) prepared by reducing unsaturated ketones (3), remove p-phenylbenzoyl, convert the resulting alcohols to tosylate, and treat them with DBU Lactol is formed, and by the Wittig reaction After introducing the chain, the resulting alcohol was oxidized at the 9-position to prepare a PGA-type compound, and the product was then reacted with a dimethyl copper complex to introduce a methyl group at the 11-position to introduce 11-methyl-PGE. It is also possible to prepare a -pressure compound and then reduce it using, for example, sodium borohydride to obtain an 11-methyl-PGE-type compound. Benzophenone-photosensitive addition of methanol of the PGE-type compound is carried out, for example, with sodium borohydride to give an 11-hydroxymethyl-PGE-type compound. 16-mono- or 16, 16-di-halo type PGE can be prepared according to the following synthetic scheme (4). Synthetic pathways for preparing compounds for use in the present invention are not limited to the methods described above, and may be modified using different protection, reduction and / or oxidation methods.

In addition, the novel compounds of the general formula (3) can be prepared according to the process as summarized in the synthetic schemes (5) to (7), P ₁ , P ₂ , in the synthetic schemes (5) to (7) P ₃ , P ₄ , P ₅ , P ₆ , P ₇ , P ₈ , Pa, Pb, Pc and Pd are protecting groups, Ra 'is lower alkyl, and Rb and Rc are the same as above.

Referring to Synthetic Scheme (5), the protected Koray lactone 40 (commercially available) having a suitable protecting group (e.g. 4-phenyl benzoyl) is oxidized (e.g., by Collins oxidation) and produced The aldehyde 41 is reacted with a (2-oxoalkyl) phosphonic acid ester having the desired R ₂ and R ₃ groups to give compound 42. The oxo group is reduced to form compound (43), and the compound (43) formed is converted to compound (44) by a protective reaction. Removal of the acyl group at the 11-position yields (45), to which another protecting group (e.g. tetrahydropyranyl) is introduced to give (46). Alkali is used to open the lactone ring to form a carboxylic acid which is then esterified to give (47). Protection group (e.g. tetrahydropyranyl) was introduced into (47) to give (48). After reducing the ester group to an aldehyde group using a reducing agent (e.g. isobutylaluminum hydride), the resultant compound is in the presence of a basic condensation reagent (e.g. lithium isopropylamide). Reaction with the chain introduction reagent (f) to form (49), (50) is prepared by deprotecting the end groups of the chain. The alcohol obtained is oxidized (eg, by Collins oxidation) and then esterified to give (51), followed by decarboxylation of the group at the 5-position to give (52). The protecting group is removed by a method according to the characteristics of this protecting group to form (53), the product is oxidized (e.g. by Collins oxidation) to form (54) and then the 15-position (eg Oxidation (e.g., by Collins oxidation) to give (55). Compound 55 is deprotected to afford (56), which is protected by only the 11-position alone (for example by Collins oxidation) and then oxidized to give (57). The product 57 thus obtained is deprotected to give the desired compound 58. In this step, when the reduction process from compound (53) to compound (54) is omitted, an unsaturated compound is obtained. The compound wherein Ra is hydrogen can be prepared by hydrolyzing the compound (58).

The chain introduction reagent (f) can be prepared by the process shown in Synthesis Scheme (6). Thus, E-caprolactone (a) is ring-opened with an alcohol capable of forming the carboxy protecting group Pa to give compound (b). The hydroxy group is protected to give compound (C) which is deprotected with compound (d) and halogenated with compound (e) and then subjected to halogen exchange reaction to give compound (f).

In another process in connection with the scheme (7), the protected co-lactone (40) is converted to the compound (59) by a similar reaction step as in (1) to (7) of the scheme (I). Compound (59) is hydrolyzed with alkali (e.g., sodium or potassium hydroxide) to form free acid (60), which is esterified (e.g. with diazomethane) to give compound (61). To obtain. The hydroxy group at position 9 is protected to give compound 62, and then the ester group is reduced (e.g., with lithium aluminum hydride) to give alcohol 63, which is then produced. The hydroxy group is oxidized to aldehyde 64 (eg, by swan oxidation). This aldehyde was subjected to ultrasonic irradiation in the presence of zinc powder and mercury chloride. Reaction with the chain introduction reagent (i) to give compound (65). This is deprotected to form compound 66 (e.g. on Pd / C) and then hydrogenated to yield compound 67. The product is then oxidized in two steps (e.g., swan oxidation and Jones oxidation) to yield compound 69 via compound 68. Acid (69) is directly deprotected with compound (71).

Chain introduction reagent (i) is prepared according to the synthetic scheme (8). Acetylene alcohol (g) is protected to form (h), which is reacted with dibromo difluoromethane to prepare (i).

Referring to Synthesis Scheme (9), Compound (73) (for example, a compound wherein Q ₁ ′ and Q ₂ ′ is hydrogen is a compound described in Synthesis Scheme I, page 37 of JP-A-52753 / 1989). Is reacted with an illide prepared from (6-carboxyhexyl) triphenylphosphonium bromide to form compound (74), which is esterified to give compound (75), followed by removal of the protecting group (76). Can be obtained. In addition, referring to the synthetic scheme (10), the compound (75) may be oxidized by Jones oxidation to form the compound (77), and then the protecting group may be removed to obtain the compound (78). Compounds wherein W is —CH ₂ ═CH—CH ₂ — or —CH ₂ —CH═CH— are compounds of (73) that are (6-carboxy-2-hexenyl) triphenylphosphonium bromide or (6-carboxy-, respectively). The compounds formed can be prepared by reacting with illi prepared from 3-hexenyl) triphenylphosphonium bromide and then treating the formed compounds in a similar manner as above.

As another example, referring to the synthetic scheme (11), the compound (80) obtained by deprotecting the commercial compound (79) was oxidized by Swern oxidation to obtain an aldehyde (81). Reaction with oxoheptyl phosphonate (eg 3, 3-dihalogenated derivative) affords compound 82. This is catalytically reduced to give compound 83, and the ketone moiety of compound 83 is reduced using sodium borohydride to produce compound 84. The resulting compound is prepared using diisobutylaluminum hydride. Further reduction yields lactol 85. This is reacted with carboxyhexylphosphonium bromide to give compound (86), which is esterified with compound (87), oxidized with compound (88) and then deprotected to give compound (78). In some cases, the obtained compound 78 can be hydrolyzed with the free acid 89. Also in Synthetic Scheme (12), the compound (87) is catalytically hydrogenated to form the compound (90), which is oxidized by Swarn oxidation to give the compound (91), and then the obtained product is deprotected to obtain the target. Compound (92) can be prepared.

In the above process, when the step of reducing the compound (82) to the compound (83) is omitted, a compound in which Z is -CH = CH- is obtained.

In addition, if a compound of formula (1) is desired in which L is a group other than OH (e.g., lower alkyl), the protecting group at the 11-position of compound (84) is removed and then the 15-position The lactone residue in the compound obtained by introducing a protecting group into is reduced to lactol, and then The chain is introduced into the product by a Wittig reaction. Then protected by the hydroxy group at the 11-position, the product was oxidized (eg Jones oxidation) to yield a 10-en-9-one compound, and the product was then reacted with lower alkyl lithium to To form a lower alkyl compound. PGD-type compounds can be obtained by oxidizing 11-deprotected compounds. PGA-type compounds can be obtained from 10-en-9-one compounds. In addition, as shown in the synthetic scheme (13), the 6-keto compound may be obtained by reacting compound (75) with N-bromosuccinimide or iodine to form compound (93) and then treating with DBU. . The 5,6-dehydro (ie, acetylene type) compound is a 8-alkoxycarbonyl-1-iodo- containing copper enoleate prepared by reacting compound (95) with a copper complex according to Synthesis Scheme (14). It can be prepared by reacting with 2-octyne. Saturated The chain introduction reagent is prepared as shown in the synthetic scheme (15).

In another embodiment, according to Synthesis Scheme 16, the hydroxy group at the 15-position of compound 84 is protected (eg, by a silyl protecting group) to form compound 97, The lactone residue of this compound was reduced with lactol to give compound (98), and then the obtained product (98) was Compound (99) is obtained by reaction with a chain introduction reagent (e.g., an illide prepared from (6-carboxyhexyl) triphenylphosphonium bromide). The carboxy group is then protected to form compound 100 and the 9-position hydroxy group is protected to form compound 101. Removal of the protecting group at the 15-position yields compound 101, which is oxidized to compound 102. Deprotection of the 9- and 11-positions affords the desired compound 104.

In addition, as shown in Synthesis Scheme (17), Compound (86) obtained as in Synthesis Scheme (11) was protected with a protecting group (e.g., benzyl) which can be removed by catalytic hydrogenation to protect Compound (87). Form, which is oxidized at the 9-position and deprotected at the 11-position to afford compound 78. Catalytic hydrogenation of this compound affords the desired compound (105).

Similar methods can be used to prepare other PC compounds.

Since the 15-keto-PG compounds have the activity of promoting the treatment of wounds, they are useful for promoting wound-treatment. Such activity can be measured by standard methods, such as by using a laboratory wound model.

The compounds used in the present invention may be useful as animal medicines and human therapeutic medicines and are generally applicable systemically or locally by oral, intravenous (including infusion), subcutaneous, rectal administration. Can be. Dosages vary depending on factors such as whether the animal or human patient is present, age, weight, symptoms to be treated, desired therapeutic effect, route of administration, duration of treatment, etc., but the dosages of 0.01 to 100 μg / eye are local (ie ocular). Satisfactory effect will be obtained when the dosage form is administered as an or sustained release or 0.001 to 500 mg / kg divided doses 2 to 4 times daily.

External compositions (including eye drops) used according to the present invention include external solutions (including eye drops), eye ointments and the like. Topical solutions (including eye drops) can be prepared by dissolving the active ingredient in a sterile aqueous solution such as saline or buffer, or by preparing a ready-to-use formulation as a combination of a solid and a solution for dissolving the solid. External ointments (including eye ointments) can be prepared by mixing the active ingredient with an ointment base.

Solid compositions of the present invention for oral administration include tablets, torches, buccal, capsules, pills, powders, granules and the like. One or more solid compositions containing at least one active substance may be mixed with one or more inert diluents such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate and Mix. The composition may contain additives other than the inert diluents such as lubricants (eg magnesium stearate), disintegrants (eg cellulose calcium gluconate), stabilizers [eg , -or Cyclodextrins, etherified cyclodextrins such as dimethyl -, Dimethyl- -, Trimetal- -Or hydroxypropyl- -Cyclodextrin), branched cyclodextrins (eg glucosyl- or maltosyl-cyclodextrins), formyl cyclodextrins, sulfur-containing cyclodextrins, microprotol or phospholipids, and the like. Such cyclodextrins can form complexes to enhance the stability of the compounds. Stability can usually be improved by forming liposomes using phospholipids. Tablets and pills can be coated with enteric or gastrointestinal digestive films, such as white sugar, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, and the like, and, if necessary, can also be coated with two or more layers. The composition may also be in the form of a capsule made of an easily absorbable material such as gelatin. In addition, where a quick effect is desired, the composition may also be in the form of a bukal in which glycerol, lactose and the like are used as a base.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and contain generally used inert diluents such as purified water or ethyl alcohol. Such compositions may contain wetting agents, suspending agents, sweetening agents, flavoring agents, flavoring agents and preservatives.

Compositions for oral administration may be syrups containing one or more active substances, and may be prepared according to well known methods.

Injection solutions for parenteral administration of the present invention include aqueous or non-aqueous solutions, suspensions and emulsions. Examples of diluents for aqueous solutions or suspensions are distilled water, physiological saline and Ringer's solution for injection. Examples of diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil), alcohols (e.g. ethanol), and polysorbates. Such compositions include preservatives, wetting agents, emulsifiers, dispersants, and the like. May contain other additives. These compositions are, for example, filtered through a bacterium-containing filter equipped with a sterilizer, or sterilized by gas sterilization or radiation sterilization. They may also be prepared by preparing sterile solid compositions and then dissolving them in sterile water for injection or sterile solvent prior to use.

Another formulation according to the invention is a rectal suppository or tablet. These formulations can be prepared by mixing one or more active compounds according to the invention with suppository bases which can be softened at body temperature, optionally containing a nonionic surfactant for improving absorbency having a suitable softening temperature.

Accordingly, the present invention also provides a method for facilitating the treatment of a corneal wound, including administering a corneal-wound-therapeutically effective amount of a 15-keto-PG compound to a subject in need thereof. Also provided is a pharmaceutical composition for promoting corneal wound treatment comprising the compound, together with the use of the compound for the manufacture of a medicament, and a pharmaceutically acceptable carrier, diluent or excipient.

The present invention will be more fully understood by reference to the following Preparation Examples, Formulation Examples and Test Examples, in which the above examples are merely to illustrate, and the above examples are merely to illustrate and limit the scope of the present invention. I do not want to.

[Production Example 1]

Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-PGE ₁ methyl ester 39

(1-1) (1S, 5R, 6R, 7R) -6-hydroxymethyl-7-tetrahydropyranyloxy-2-oxabicyclo [3. 3. Preparation of 0] octan-3-one- (29)

To a solution of commercial Corey lactone (THP-type, 37.9 g) in tetrahydrofuran was added a solution of tetrabutylammonium fluoride (1.0 M, 300 mL) in tetrahydrofuran, and the resulting mixture was allowed to come to room temperature. Stir for 3 hours.

The reaction mixture is then concentrated under reduced pressure and the residue is column chromatographed to give the title compound (29). Yield: 21.70 g (82.8%).

(1-2) (1S, 5R, 6R, 7R) -6-{(E) -4, 4-difluoro-5-oxo-2-octenyl} -7-tetrahydropyranyloxy-2- Oxabicyclo [3. 3. Preparation of 0] octane-3-one- (31)

Oxalyl chloride solution (2.0 M, 45.5 mL) in methylene chloride is diluted with methylene chloride under argon atmosphere at -78 ° C. Dimethyl sulfoxide (12.9 mL) was added dropwise to this solution, and the resulting mixture was stirred for 10 minutes. (1S, 5R, 6R, 7R) -6-hydroxymethyl-7-tetrahydropyranyloxy-2-oxabicyclo in methylene chloride [3. 3. Add a solution of 0] octan-3-one- (29) (11.65 g) dropwise and stir the mixture for 30 minutes. Triethylamine (56 mL) is then added dropwise and further stirred for 1 hour. The reaction mixture is treated in a conventional manner to give aldehyde 30 as a crude product.

To a solution of thallium ethoxide in methylene chloride (3.26 ml) is added dimethyl 3, 3-difluoro-2-oxoheptylphosphonate (11.9 g) under an argon atmosphere and the resulting mixture is stirred for 1 hour. After the solution is cooled to 0 ° C., a solution of the obtained aldehyde 30 in methylene chloride is added dropwise to the solution and the mixture is stirred at room temperature for 14 hours. The reaction mixture is filtered by treatment with acetic acid, celite and saturated aqueous potassium iodide. The filtrate is treated in a conventional manner and the crude product is column chromatographed to give the title compound (31). Yield: 7.787 g (44.3%).

(1-3) (1S, 5R, 6R, 7R) -6- (4, 4-difluoro-5-oxooctyl) -7-tetrahydropyranyloxy-2-oxabicyclo [3. 3. Preparation of 0] octane-3-one- (32)

(1S, 5R, 6R, 7R) -6-{(E) -4, 4-difluoro-5-oxo-2-octenyl) -7-tetrahydropyranyloxy-2-oxabie in ethyl acetate Cyclo [3. 3. Add 5% Pd / C (catalyst amount) to a solution of 0] octan-3-one- (31) (5.57 g) and shake the resulting mixture for 7 hours at room temperature under hydrogen atmosphere. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to afford the title compound 32 as crude product. Yield: 5.48 g (97.8%).

(1-4) (1S, 5R, 6R, 7R) -6- {4, 4-difluoro-5 (RS) -hydroxyoctyl} -7-tetrahydropyranyloxy-2-oxabicyclo [ 3. 3. Preparation of 0] octane-3-one- (33)

(1S, 5R, 6R, 7R) -6- (4, 4-difluoro-5-oxooctyl) -7-tetrahydropyranyloxy-2-oxabicyclo [3. 3. To a solution of 0] octan-3-one- (32) (5.48 g) is added sodium borohydride (0.800 g) at 0 ° C. and the resulting mixture is stirred for 10 minutes. The reaction mixture is treated in a conventional manner and the crude product obtained is column chromatographed to give the title compound (33). Yield: 5.46 g (99.5%).

(1-5) Preparation of 16, 16-difluoro-13, 14-dihydro-11-tetrahydropyranyloxy-PGF _2α methyl ester (36)

(1S, 5R, 6R, 7R) -6- {4, 4-dihydro-5 (RS) -hydroxyoctyl} -7-tetrahydropyranyloxy-2-oxabicyclo [3. In toluene. 3. Cool a solution of 0] octan-3-one- (33) (2.579 g) to −78 ° C. under argon atmosphere. To this solution was added dropwise a solution of diisobutylaluminum hydride (1.5 M, 9.6 mL) in toluene and stirred for 30 minutes. The reaction mixture is treated with methanol and saturated aqueous Rochelle salt. The solution is then treated in a conventional manner to yield lactol 34 as a crude product.

To a suspension of 4-carboxybutyl triphenyl phosphine bromide (11.72 g) in tetrahydrofuran was added dropwise a solution of potassium t-butoxide in tetrahydrofuran (1.0M, 52.84 mL) under an argon atmosphere, resulting in The mixture is stirred for 20 minutes. The solution is cooled to 0 ° C. and mixed with a solution of lactol 34 in tetrahydrofuran. The resulting mixture is stirred at room temperature for 15 hours and then treated in a conventional manner to give carboxylic acid 35 as a crude product.

To a solution of carboxylic acid (35) in acetonitrile under 1,8-diazabicyclo [5. 4. Undec-7-ene (DBU) (4.0 mL) and methyl iodide (1.7 mL) are added and the resulting solution is stirred at 60 ° C. for 30 h. The solution is treated in a conventional manner and the product is column chromatographed to give the title compound 36. Yield: 2.737 g (84.5%).

(1-6) Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-11-tetrahydropyranyloxy-PGF ₂ methyl ester (37)

To a solution of Collins' reagent prepared from chromic anhydride (16.18 g) and pyridine (26.2 mL) in methylene chloride in a conventional manner, 16, 16-difluoro-13, in methylene chloride at -20 ° C under an argon atmosphere. A solution of 14-dihydro-11-tetrahydropyranyloxy-PGF _2α methyl ester 36 (2.646 g) is added. The resulting mixture is stirred at the same temperature for 2 hours and at -5 ° C for 9 hours. The solution is treated with ether and sodium hydrogen sulfate and filtered. The filtrate is concentrated under reduced pressure and the residue is column chromatographed to give the title compound (37). Yield: 1.890 g (64.4%).

(1-7) Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-PGF ₂ methyl ester (38)

16, 16-difluoro-13, 14-dihydro-15-keto-11-tetrahydroxypyranyloxy-PGF ₂ methyl ester (37) (2.809 g) was added with acetic acid: water: tetrahydrofuran (3: 1: 1) and the resulting solution is stirred at 60 ° C. for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed to give the title compound (38). Yield: 1.755 g (75.5%).

(1-8) Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-PGF ₁ methyl ester (39)

To the solution of 16, 16-difluoro-13, 14-dihydro-15-keto-PGF ₂ methyl ester (38) (1.755 g) in ethyl acetate was added Pd / C (catalyst amount) and the mixture was hydrogen atmosphere. Shake at room temperature for 6 hours. The reaction mixture is filtered. The filtrate is concentrated and the residue is column chromatographed to give the title compound (39). Yield: 1.655 g (93.8%).

¹ H NMR (CDCl ₃ ) 0.87 (3H, t, J = 7 Hz), 1.15-2.05 (23H, m), 2.11-2.30 (3H, m), 2.50 (1H, dd, J = 7.5 and 17 Hz), 3.10-3.20 (1H, br) , 3.71 (3H, s), 4.05-4.20 (1H, m)

MS (DI-EI) m / z 404 (M ⁺ ), 355 (M ⁺ -H ₂ O-CH ₃ O), 297 (M ⁺ -C ₅ H ₉ F ₂ )

[Production Example 2]

Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-PGF ₁ (39 ')

(2-1) Preparation of (15RS) -16, 16-difluoro-13, 14-dihydro-11-0-tetrahydropyranyl-PGF _2α benzyl ester (36)

DBU (2.1 mL) and benzyl in a solution of 16, 16-difluoro-13, 14-dihydro-11-0-tetrahydropyranyl-PGF _2α (35) (2.33 g) in dichloromethane (300 mL) Bromide (2.2 mL) is added and the resulting mixture is stirred at rt for 1.5 h. The reaction mixture is treated in a conventional manner and the crude product is purified by silica-gel column chromatography to afford the title compound 36. Yield: 2.522 g (96.1%)

(2-2) Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-11-0-tetrahydropyranyl-PGF ₂ benzyl ester (37)

Collins reagent was prepared using chromic anhydride (13.5 g) and pyridine (21.8 mL) in dichloromethane (300 mL), including celite (40 g) and (15RS) -16, 16-difluoro-13, 14-Dihydro-11-0-tetrahydropyranyl-PGF _2α benzyl ester 36 (2.550 g) is added. The reaction mixture is treated in a conventional manner and the crude product is purified by silica-gel column chromatography to afford the title compound 37. Yield: 1.911 g (78.6%)

(2-3) Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-PGF ₂ benzyl ester (38)

16, 16-difluoro-13, 14-dihydro-15-keto-11-0-tetrahydropyranyl-PGF ₂ benzyl in a mixed solvent of acetic acid: THF: water (3: 1: 1, 50 mL) Ester 37 (1.550 g) is dissolved and the solution is kept at 50 ° C. for 4 hours. The reaction mixture is treated in a conventional manner and the crude product is purified by silica-gel column chromatography to give the title compound (38). Yield: 1.225 g (92.9%)

(2-4) Preparation of 16, 16-difluoro-13, 14-dihydro-15-keto-PGF ₁ (39 ')

To a solution of 16, 16-difluoro-13, 14-dihydro-15-keto-PGF ₂ benzyl ester (38) (0.844 g) in ethyl acetate (30 mL) was added 5% Pd / C and the mixture was Shake under hydrogen atmosphere. The reaction mixture is treated in a conventional manner and the crude product is purified by silica-gel column chromatography to afford the title compound 43. Yield: 0.404 g

¹ H NMR (CDCl ₃ ) 0.94 (t, 3H, J = 7.5 Hz), 1.20-2.70 (m, 26H), 4.19 (m, 3H), 4.80 (br, 2H).

MS (DI-EI) m / z 390 (M ⁺ ), 372 (M ⁺ -H ₂ O), 354 (M ⁺ -2H ₂ O)

[Manufacture example 3]

5 (RS) -Fluoro-13, 14-dihydro-6, 15-diketo-PGE ₁ methyl ester [IUPAC Nomenclature: 5 (RS) -Fluoro-7-{(1R, 2S, 3S) -3 Preparation of -hydroxy-2- (3-oxooctyl-5-oxocyclopentyl} -6-oxoheptanoate]

(3-1) (1S, 5R, 6R, 7R) -6-[(E) -3-oxo-1-octenyl] -7- (4-phenyl) benzoyloxy-2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (42)

Collins oxidizes commercially available (-)-koray lactone (40) (10.0 g) in dichloromethane to form aldehyde (41), which is prepared from dimethyl (2-oxoheptyl) phosphonate (6.21 g). React with anions. The reaction mixture is treated in a conventional manner and the crude product obtained is column chromatographed to give the title compound 42. Yield: 7.45 g (60%)

(3-2) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -hydroxy-1-octenyl] -7- (4-phenyl) benzoyloxy-2-oxabi Cyclo [3. 3. 0] Preparation of Octane-3-one (43)

(1S, 5R, 6R, 7R) -6-[(E) -3-oxo-1-octenyl] -7- (4-phenyl) benzoyloxy-2-oxabicyclo [3. 3. To a solution of [0] octane-3-one (42) (7.45 g) was added cerium chloride (III) heptahydrate (6.84 g) and sodium borohydride (0.69 g) at -20 ° C and the mixture was stirred for 1 hour. Stir.

The reaction mixture is treated in a conventional manner and the crude product obtained is column chromatographed to give the title compound 43 as a compound of diastereomer. Yield: 7.64 g (theoretical value)

(3-3) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyl-dimethylsilyloxy-1-octenyl] -7- (4-phenyl) benzoyloxy -2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (44)

(1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -hydroxy-1-octenyl] -7- (4-phenyl) benzoyloxy-2-oxabi in dimethyl formamide Cyclo [3. 3. Add imidazole (2.27 g) and t-butyldimethylsilyl chloride (3.78 g) to a solution of 0] octan-3-one (43) (7.65 g) and stir the mixture for 1 hour.

The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 44 as a mixture of diastereomers. Yield: 7.49 g (80%)

(3-4) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -7-hydroxy-2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (45)

(1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -7- (4-phenyl) benzoyloxy-2-oxabicyclo [3. 3. A mixture of 0] octane-3-one (44) (7.49 g), potassium carbonate (1.10 g) a and methanol is stirred at room temperature for 16 hours. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 45 as a mixture of diastereomers. Yield: 4.69 g (92%)

(3-5) (1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -7-tetrahydropyranyloxy-2- Oxabicyclo [3. 3. 0] Preparation of Octane-3-one (46)

(1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -7-hydroxy-2-oxabicyclo [in methylene chloride [ 3. 3. To a solution of octane-3-one (45) (4.69 g) was added dihydropyran (5.17 g) and pyridinium p-toluenesulfonate (0.77 g), and the resulting mixture was allowed to stand at room temperature for 16 hours. Stir. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 46 as a mixture of diastereomers. Yield: 5.37 g (94%)

(3-6) Methyl 2-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -5-hydroxy-tetra Preparation of Hydropyranyloxy-cyclopentyl} acetate (47)

(1S, 5R, 6R, 7R) -6-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -7- in a mixed solvent of methanol and water (4: 1) Tetrahydropyranyloxy-2-oxabicyclo [3. 3. Lithium hydroxide (0.33 g) is added to a solution of 0] octan-3-one (46) (1.85 g). The resulting mixture is stirred at rt for 16 h. The reaction mixture is neutralized and extracted with ethyl acetate. The organic layer is then separated and an ether solution of diazo methane is added. The resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 47 as a mixture of diastereomers. Yield: 1.82 g (92%)

(3-7) Methyl 2-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -3, 5-bis- Preparation of Tetrahydropyranyl-oxy-cyclopentyl} acetate 48

Methyl 2-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -5-hydroxytetra in methylene chloride Dihydropyran (3.75 g) and pyridinium p-toluenesulfonate (0.56 g) were added to a solution of hydropyranyloxy-cyclopentyl} acetate (47) (4.45 g), and the resulting mixture was stirred at room temperature for 16 hours. Stir. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 48 as a mixture of diastereomers. Yield: 4.24 g (74%)

(3-8) Methyl 6-benzoyloxy-2 (RS)-{2-[(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1 Preparation of -Octenyl] -3,5-bis-tetrahydropyranyloxy-cyclopentyl} -1 (RS) -hydroxyethyl} -2 (RS) -fluorohexane acetate (49)

Methyl 2-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -3, 5-bis-tetrahydropyranyloxy Toluene solution of -cyclopentyl} acetate 48 (0.5 g) was added toluene solution of DIBAL-H (1.5 M, 1.43 mL) at -78 ° C, and the resulting mixture was stirred for 1 hour. The reaction mixture is treated in a conventional manner to give aldehyde as a crude product.

A solution of LDA in tetrahydrofuran (0.94 mmol) prepared by a conventional method is cooled to -78 ° C, to which methyl 6-benzoyloxy-2 (RS) -fluorohexanoate (f) (0.23 g ) The resulting mixture is stirred for 10 minutes and a solution of crude aldehyde in tetrahydrofuran is added. The reaction mixture is heated to room temperature and stirred at the same temperature for 1 hour. The crude product obtained by conventional methods is subjected to silica gel column chromatography to give the title compound (49) as a mixture of diastereomers. Yield: 0.51 g (74%)

(3-9) Methyl 2 (RS)-{2-[(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl]- Preparation of 3, 5-bis-tetrahydropyranyloxy-cyclopentyl} -1 (RS) -hydroxyethyl} -2 (SR) -fluoro-6-hydroxyhexanoate (50)

Methyl 6-benzoyloxy-2 (RS)-{2-[(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-jade in methanol Tenyl] -3,5-bis-tetrahydropyranyloxy-cyclopentyl] -1 (RS) -hydroxyethyl-2 (RS) -fluorohexaneacetate 49 (2.48 g) in methanol Calcium carbonate (2.47 g) is added and the resulting mixture is stirred at room temperature for 24 hours. The crude product obtained by conventional methods is subjected to silica gel column chromatography to give the title compound (50). Yield: 1.50 g (69%)

(3-10) 7-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -3, 5-bis-tetra Preparation of Hydropyranyl-oxocyclopentyl] -5- (RS) -methoxycarbonyl-5 (SR) -fluoro-6-oxoheptanoate (51)

Methyl 2 (RS)-{2-[(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -3, 5-bis -Tetrahydropyranyloxy-cyclopentyl] -1 (RS) -hydroxyethyl} -2 (SR) -fluoro-6-hydroxyhexanoate (50) (1.23 g) under -50 ° C under an argon atmosphere. Collins oxidizes for 4.5 hours. The crude product, obtained by conventional customary methods, is dissolved in ether and a solution of diazomethane in ether is added. The resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 51 of a mixture of diastereomers. Recover unreacted starting material (50). (0.41 g, recovery: 33%). Yield: 0.60 g (47%)

(3-11) Methyl 7-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -3, 5-bis- Tetrahydropyranyloxocyclopentyl] -5- (RS) -Fluoro-6-oxo-heptanoate 52

7-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -3, 5-bis-tetrahydropyranyloxycyclo Pentyl] -5- (RS) -methoxycarbonyl-5 (SR) -fluoro-6-oxoheptanoate (51) (0.80 g) was converted to dimethyl sulfoxide, sodium chloride and water (50: 2.8: 1). Is dissolved in a mixture of and the resulting mixture is stirred for 1.5 h at 135-140 ° C. under an argon atmosphere. The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give the title compound 52 of a mixture of diastereomers. Yield: 0.55 g (75%)

(3-12) Methyl 5 (RS) fluoro-7-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-hydroxy-1-octenyl] -3 , 5-bis-tetrahydropyranyloxocyclopentyl] -6-oxoheptanoate (53)

Methyl 7-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-butyldimethylsilyloxy-1-octenyl] -3, 5-bis- in tetrahydrofuran Tetra-n-butyl in tetrahydrofuran (1M, 23 mL) in a solution of tetrahydropyranyloxocyclopentyl] -5- (RS) -fluoro-6-oxo-heptanoate (52) (0.52 g). A solution of ammonium fluoride is added and the resulting mixture is stirred at room temperature for 40 hours. The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give the title compound (53). Yield: 0.34 g (67%)

(3-13) Methyl 5 (RS) fluoro-7-{(1R, 2R, 3R, 5S) -2- [3 (RS) -hydroxy-1-octyl] -3, 5-bistetra-hydro Preparation of pyranyloxycyclopentyl] -6-oxoheptanoate 54

Methyl 5 (RS) fluoro-7-{(1R, 2R, 3R, 5S) -2-[(E) -3 (RS) -t-hydroxy-1-octenyl] -3 in ethyl acetate, 5% Pd / C (0.06 g) was added to a solution of 5-bis-tetrahydropyranyloxycyclopentyl] -6-oxoheptanoate (53), and the resulting mixture was stirred for 16 hours at room temperature under hydrogen atmosphere. do. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 54 as a mixture of diastereomers. Yield: 0.30 g (88%)

(3-14) Methyl 5 (RS) -fluoro-7-{(1R, 2R, 3R, 5S) -2- [3-oxo-octyl] -3, 5-bistetrahydropyranyloxy-cyclopentyl ] -6-oxoheptanoate (55)

Methyl 5 (RS) -fluoro-6-oxo-7-{(1R, 2R, 3R, 5S) -2- [3 (RS) -hydroxy-1-octyl] -3, 5-bis in acetone To the solution of tetra-hydropyranyloxycyclopentyl] -6-oxoheptanoate (54) (0.30 g) was added Jones reagent (2.60 M, 0.6 mL) and the resulting mixture was stirred at -30 ° C. for 1.5 h. do. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 55 as a mixture of diastereomers. Yield: 0.24 g (80%)

(3-15) Methyl 5 (RS) -fluoro-7-{(1R, 2R, 3R) -3-t-butyldimethylsilyloxy-5-oxo-2- (3-oxo-octyl) -cyclopentyl ] -6-oxoheptanoate (57)

Methyl 5 (RS) -fluoro-6-oxo-7-{(1R, 2R, 3R, 5S) -2- [3-oxo-octyl] -3, 5-bistetrahydropyranyloxy-cyclopentyl] -6-oxoheptanoate 55 (0.24 g) is dissolved in a mixed solvent of acetic acid, tetrahydrofuran and water (3: 1: 1) and the resulting mixture is stirred at 45 ° C. for 4.5 h. The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give the diol product 56 (0.15 g).

To a solution of diol product 56 (0.15 g) in dimethylformamide is added imidazole (0.35 g) and t-butyl-dimethylsilyl chloride (0.38 g) and the resulting mixture is stirred at room temperature for 5 hours. The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give a monosilyl product (0.135 g).

Monosilyl product (0.135 g) is oxidized Collins in methylene chloride for 15 minutes at room temperature. The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give the title compound (57). Yield: 0.10 g (49%, starting from compound (55))

(3-16) Preparation of 5 (RS) -Fluoro-13, 14-dihydro-6, 15-diketo-PGE ₁ methyl ester (58)

Methyl 5 (RS) -fluoro-7-{(1R, 2R, 3R) -3-t-butyldimethylsilyloxy-5-oxo-2- (3-oxo-octyl) -cyclopentyl] in dichloromethane To a solution of -6-oxoheptanoate 57 (0.05 g) is added a solution of hydrogen fluoride-pyridine (70:30, 0.40 mL) and the resulting mixture is stirred at room temperature for 7 hours. The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give the title compound (58). Yield: 0.38 g (98%)

¹ H NMR (CDCl ₃ ): 0.87 (3H, t, J = 6.8 Hz), 1.16-2.05 (14H, m), 2.23-3.15 (11H, m), 3.66 (3H, s), 3.98-4.12 (1H, m), 4.62-4.70 ( 0.5 H, m), 4.85-4.95 (0.5 H, m).

Preparation of Starting Material: Methyl 6-benzoyloxy-2 (RS) -fluoro-hexanoate (f)

(1) Preparation of benzyl 6-hydroxyhexanoate (b)

A mixture of caprolactone (a) (40 g), benzyl alcohol and p-toluenesulfonic acid monohydrate (0.7 g) is stirred at 100 ° C. for 16 h. The reaction mixture is treated in a conventional manner and distilled under reduced pressure (1 mmHg, 140-154 ° C.) to afford the title compound (b). Yield: 27.37 g (35%)

(2) Preparation of benzyl 6-benzylyloxyhexanoate (C)

To a solution of benzyl 6-hydroxyhexanoate (b) (27.37 g) in methylene chloride is added 4-dimethyl aminopyridine (19.5 g) and benzoyl chloride (19.53 g) and the resulting mixture is stirred for 2 hours. The reaction mixture is treated in a conventional manner and distilled under reduced pressure (1 mmHg, 190-215 ° C.) to afford the title compound (c). Yield: 38.09 g (95%)

(3) Preparation of 6-benzoyloxy-hexanoic acid (d)

To a solution of 6-benzoyloxy-hexanoate (c) (38.09 g) in ethyl acetate is added 5% Pd / C (3 g) and the resulting mixture is stirred for 24 h under a hydrogen atmosphere. The crude product obtained by treatment in a conventional manner is distilled under reduced pressure (1 mmHg, 182-192 ° C.) to give the title compound (d). Yield: 4.92 g (90%)

(4) Preparation of methyl 6-benzoyloxy-2 (RS) -bromo-hexanoate (e)

Thionyl chloride (22 mL) is added dropwise to 6-benzoyloxyhexanoic acid (d) (14.92 g) and the resulting mixture is stirred at 65 ° C. for 1 hour. Carbon tetrachloride (50 mL), N-bromo-succinimide (22.5 g) and 48% hydrobromic acid (5 drops) are added to the reaction mixture, and the resulting mixture is stirred at 85 ° C. for 20 hours. The reaction mixture is cooled and filtered to remove the solid product. The filtrate is concentrated under reduced pressure. The obtained residue is dissolved in methanol and the resulting mixture is stirred at room temperature. The crude product obtained by treatment in a conventional manner is subjected to silica gel chromatography to give the title compound (e). Yield: 14.02 g (67%)

(5) Preparation of methyl 6-benzoyloxy-2 (RS) -fluorohexanoate (f)

A mixture of methyl 6-benzoyloxy-2 (RS) -bromohexanoate (e) (14.02 g), potassium fluoride (12.59 g) and acetamide (12.3 g) is stirred at 105 ° C. for 6 hours. The crude product obtained by treatment in a conventional manner is subjected to silica gel chromatography to give the title compound (f) and 6-benzoyloxyhexanoate (g) (3.11 g, yield: 29%). Yield: 5.28 g (46%)

¹ H NMR (CDCl ₃ ) 1.55-2.18 (6H, m), 3.79 (3H, s), 4.33 (2H, t, J = 7 Hz), 4.77-4.86 (0.5H, m), 5.05-5.12 (0.5H, m), 7.40- 7.62 (3H, m), 8.00-8.10 (2H, m).

[Production Example 4]

Preparation of 5, 5-difluoro-13, 14-dihydro-6, 15-diketo-PGE ₁ methyl ester 72

(4-1) (1S, 5R, 6R, 7R) -6-[(E) -3-oxo-1-octenyl] -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (42)

Korey-lactone (40) (10.0 g) dissolved in dichloromethane (160 mL) was dissolved in DMSO (79.2 g), dicyclohexylcarbodiimide (24.0 g), pyridine (2.3 mL) and trifluoroacetic acid (1.1 mL). Moffatt oxidation with) yields the co-lactone aldehyde (2a). Separately, dimethyl (2-oxoheptyl) phosphonate anion was prepared from dimethyl (2-oxoheptyl) phosphonate (6.31 g) and sodium hydride (60%, 0.13 g) in dichloromethane, and the aldehyde obtained in advance (160 mL) solution is added dropwise, and the resulting mixture is stirred at room temperature for 11.5 hours. The crude product obtained by treatment in a conventional manner is subjected to silica gel chromatography to give the title compound (42). Yield: 10.8 g (85.3%)

(4-2) (1S, 5R, 6R, 7R) -6- [3-oxo-1-octenyl] -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3. 3. Preparation of 0] octane-3-one (4a)

(1S, 5R, 6R, 7R) -6-[(E) -3-oxo-1-octenyl] -7- (4-phenylbenzoyloxy) -2-oxabicyclooctane in ethyl acetate (150 mL) [3. 3. A mixture of 0] -3-one (42) (10.8 g) and 5% Pd / C (1.02 g) is stirred under hydrogen atmosphere for 3 hours. The reaction mixture is treated in a conventional manner to afford the title compound 4a. Yield: 8.20 g

(4-3) (1S, 5R, 6R, 7R) -6- [3, 3-ethylenedioxyoctyl-7- (4-phenylbenzoyloxy) -2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (5)

(1S, 5R, 6R, 7R) -6- (3-oxo-1-octenyl) -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3. in toluene (100 mL). 3. Add ethylene glycol (23.0 g) and p-toluenesulfonic acid (0.41 g) to a solution of 0] octan-3-one (4a) (8.20 g) and reflux the resulting mixture for 4 hours. The water formed during the reaction is removed by azeotropic distillation. The reaction mixture is treated in a conventional manner and silica gel column chromatography to give the title compound 5a. Yield: 8.23 g (91.3%)

(4-4) (1S, 5R, 6R, 7R) -6- (3, 3-ethylene-dioxyoctyl) -7-hydroxy-2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (6a)

(1S, 5R, 6R, 7R) -6- (3, 3-ethylenedioxyoctyl-7- (4-phenylbenzoyloxy) -2-oxabicyclo in methanol (200 mL) [3. 0] Potassium carbonate (1.15 g) is added to a solution of octane-3-one (5a) (8.20 g), the resulting mixture is stirred overnight, and then acetic acid (1 ml) is added to the crude product. Silica gel column chromatography was carried out to give the title compound (6a) yield: 4.70 g (90.0%).

(4-5) (1S, 5R, 6R, 7R) -6- (3, 3-ethylenedioxyoctyl) -7-tetrahydropyranyloxy-2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (59)

(1S, 5R, 6R, 7R) -6- (3, 3-ethylene-dioxyoctyl-7-hydroxy-2-oxabicyclo [3.3.0] octane-3 in dichloromethane (200 mL) The solution of -one 6a (4.70 g) is cooled on ice, dihydropyran (2.41 g) and p-toluenesulfonic acid (0.23 g) are added and the resulting mixture is stirred for 1.5 h. The crude product obtained by the method was subjected to silica gel column chromatography to give the title compound 59. Yield: 5.54 g (93%)

(4-6) Methyl 2-[(1S, 2R, 3R, 5S) -2- (3, 3-ethylenedioxyoctyl) -3- (tetrahydropyranyloxy) -5-hydroxycyclopentyl] acetate Manufacture of 61

(1S, 5R, 6R, 7R) -6- (3, 3-ethylenedioxyoctyl-7-tetrahydropyranyloxy-2-oxabicyclo [3.3.0] octan-3-one (59) (5.54 g) is dissolved in methanol (61 mL) and 5% aqueous potassium hydroxide (37 mL) is added The resulting mixture is stirred for 30 min at 50 ° C. The reaction mixture is cooled to 0.5 N while cooling on ice. The acid (60) obtained by neutralization with aqueous hydrochloric acid and treated by a conventional method is obtained with diazomethane to give the title compound (61) .Yield: 5.74 g

(4-7) Methyl 2-[(1S, 2R, 3R, 5S) -2- (3, 3-ethylenedioxyoctyl-3- (tetrahydropyranyloxy) -5- (t-butylsilyloxy) Preparation of Cyclopentyl] Acetate 62

Methyl 2-[(1S, 2R, 3R, 5S) -2- (3, 3-ethylenedioxyoctyl) -3- (tetrahydropyranyloxy) -5-hydroxycyclopentyl] in DMF (80 mL) To the solution of acetate 61 t-butyldimethylsilyl chloride (2.11 g) and imidazole (0.95 g) are added and the resulting mixture is stirred. The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give the title compound (62). Yield: 5.41 g (71.2%)

(4-8) 2-[(1S, 2R, 3R, 5S) -2- (3, 3-ethylenedioxyoctyl) -3- (tetrahydropyranyloxy) -5- (t-butyldimethylsilyloxy ) Cyclopentyl] ethanol (63)

Methyl 2-[(1S, 5R, 6R, 7R) -2- (3, 3-ethylenedioxyoctyl) -3- (tetrahydropyranyloxy) -5- (t-butyldimethylsilyloxy) -cyclopentyl ] Acetate 62 is reduced with lithium aluminum hydride in ether (150 mL). The crude product obtained by treatment in a conventional manner is subjected to silica gel column chromatography to give the title compound (63). Yield: 4.81 g (93.8%)

(4-9) 2-[(1S, 5R, 6R, 7R) -2- (3, 3-ethylenedioxyoctyl) -3- (tetrahydropyranyloxy) -5- (t-butyldimethylsilyloxy ) Cyclopentyl] acetaldehyde (64)

2-[(1S, 5R, 7R, 7R) -2- (3, 3-ethylenedioxyoctyl) -3- (tetrahydropyranyloxy) -5- (t-butylsilyl in dichloromethane (50 mL) A solution of oxy) cyclopentyl] ethanol (63) was swan-oxidized using oxalyl chloride (1.78 g), DMSO (2.19 g) and triethylamine (4.37 g) to afford the title compound (12). Yield: 4.60 g (96.0%)

(4-10) 1-[(1R, 2R, 4S, 5R) -2-tetrahydropyranyloxy) -4-t-butylsilyloxy-5- {2 (RS) -hydroxy-3, 3- Preparation of Difluoro-7-t-butyldimethylsilyloxy-4-heptinyl} -cyclopentyl] -3, 3-ethylenedioxy-octane 65

2-[(1S, 2R, 3R, 5S) -2- (3, 3-ethylenedioxyoctyl) -3- (tetrahydropyranyloxy) -5- (t-butylsilyloxy in THF (25 mL) Activated zinc powder (2.54 g) was added to a solution of cyclopentyl] acetaldehyde (64) (1.00 g) and cooled on ice, while 1-boromo, 1-difluoro-5- in THF (50 mL). A solution of (t-butyl-dimethylsilyloxy) -2-pentin (i) (0.92 g) is added dropwise to the resulting mixture. Mercury chloride (0.11 g) is added to the resulting solution, and the resulting mixture is stirred under ultrasonic irradiation. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (65). Yield: 1.40 g (95.9%)

(4-11) 1-[(1R, 2R, 4S, 5R) -2-tetrahydropyranyloxy-4-hydroxy-5- {2 (RS), 7-dihydroxy-3, 3-di Fluoro-4-heptyl} -cyclopentyl] -3, 3-ethylenedioxyoctane (67)

1-[(1R, 2R, 4S, 5R) -2-tetrahydropyranyloxy-4-t-butylsilyloxy-5- {2 (RS) -hydroxy-3, 3- in THF (15 mL) A solution of difluoro-7-t-butyldimethylsilyloxy-4-heptinyl} -cyclopentyl] -3, 3-ethylenedioxy-octane (65) (0.96 g) was cooled on ice and tetrabutylammonium After addition of fluoride (1M, 0.57 mL), the resulting mixture is stirred for 12 hours. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel chromatography to give triol (66).

Triol 66 is catalytically hydrogenated on 5% Pd / C (0.06 g) in acetate (50 mL). The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel chromatography to give the title compound (67). Yield: 0.487 g (98.6%)

(4-12) Preparation of 5, 5-difluoro-6-keto-11-pyranyloxy-15, 15-ethylenedioxy-13, 14-dihydro-PGE ₁ methyl ester (70)

1-[(1R, 2R, 4S, 5R) -2-tetrahydropyranyloxy-4-hydroxy-5- {2 (RS), 7-dihydroxy-3, 3 in dichloromethane (18 mL) A solution of -difluoro-4-heptinyl} -cyclopentyl] -3, 3-ethylenedioxyoctane (67) (0.487 g) was converted to oxalyl chloride (1.17 g), DMSO (1.51 g) and triethylamine Swan oxidation using (3.1 g) afforded diketoaldehyde 68 (0.321 g, Y: 67.3%).

The obtained diketoaldehyde 68 (0.212 g) was oxidized Jones using Jones reagent (2.67M, 153.6) at a temperature of -50 ° C to -40 ° C to give carboxylic acid (69), which yielded a methyl ester. React with diazomethane to The crude product obtained is subjected to silica gel column chromatography to give the title compound (70). Yield: 0.152 g (67.8%)

(4-13) Preparation of 5, 5-difluoro-13, 14-diketo-PGE ₁ methyl ester 72

5, 5-difluoro-6-keto-11-pyranyloxy-13, 14-dihydro-15, 15-ethylene in a mixed solvent (6 mL) of acetic acid / THF / water (2/1/1) A solution of deoxy-PGE ₁ methyl ester 70 (0.152 g) is maintained at 45-50 ° C. for 2.5 hours. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 72. Yield: 0.101 g (87.0%)

^* 13, 14-dihydro-6, 15-diketo -5, -PGE _1-methyl ester 5-difluoro

¹ H NMR (CDCl ₃ ) 0.88 (t, 3H, J = 6.6 Hz), 1.10-1.40 (m, 4H), 1.45-2.20 (m, 10H), 2.20-3.15 (m, 11H), 3.67 (s, 3H), 4.00-4.18 ( m, 1 H).

MS (DI-EI) m / z 418 (M ⁺ ), 400 (M ⁺ -H ₂ O), 360 (M ⁺ -HF-H ₂ O), 99 (C ₆ H ₁₁ CO ⁺ )

Preparation of Starting Material: 5- (t-Butyldimethylsiloxy) -1-bromo-1, 1-difluoro-3-pentin (i)

(1) Preparation of 5- (t-butyldimethylsiloxy) -3-pentin (h)

To a solution of 3-butyn-1-ol (g) in DMF (80 mL) was added t-butyldimethylsilyl chloride (21.5 g) and imidazole (10.6 g), and the obtained crude product was distilled off to obtain the title compound (h). ). Yield: 17.4 g (66%)

(2) Preparation of 5- (t-butyl-dimethylsiloxy-1-bromo-1, 1-difluoro-3-pentin (i)

A solution of 5- (t-butyldimethylsiloxy) -3-pentin (h) (8.00 g) in THF (100 mL) was cooled to -20 ° C and n-butyl lithium (1.6 M, 27.1 mL) was added dropwise. do. The resulting mixture is stopped at 0 ° C., a solution of dibromodifluoromethane in THF (50 mL) is added and the mixture is stirred for 2 hours. The reaction mixture is treated in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (i). Yield: 3.67 g (27%)

Production Example 5

20-ethyl-decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-15-keto-PGF ₂ isopropyl ester (76) [IUPAC nomenclature: isopropyl (Z) -9- (1R) Preparation of [[(2R, 3R, 5S) -3, 5-dihydroxy-2- (3-oxodecyl) cyclopentyl] -7-nonenoate]

(5-1) (Z) -9- (1R)-[(2R, 3R, 5S) -2- (3, 3-ethylenedioxydecyl) -5-hydroxy-3- (tetrahydropyranyloxy Preparation of Cyclopentyl] -7-Nenonoic Acid (74)

Sodium hydride (60%, 0.422 g) is washed with hexane under argon atmosphere. To this was added dimethyl sulfoxide (DMSO, 10 mL) and the resulting mixture was kept at 60 ° C. for 3 hours. After cooling to room temperature, the resulting mixture is treated with 6-carboxyhexyltriphenylphosphonium bromide (2.49 g), stirred at room temperature for 2 hours and then at 45 ° C. for 1 hour and then poured into ice water. The resulting mixture is worked up according to the usual procedure to afford the title compound 74. Yield: 1.68 g

(5-2) Isopropyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- (3, 3-ethylenedioxydecyl) -5-hydroxy-3- (tetrahydropyra Preparation of Nyloxy) cyclopentyl] -7-nonenoate 75

Compound (74) (1.68 g) was purified by 1, 8-diazabicyclo [5. 4. Esterize in a conventional manner using 0] -7-undecene (DBU, 0.78 mL) and isopropyl iodide (0.35 mL) in acetonitrile (15 mL). The residue is subjected to silica gel column chromatography to give the title compound (75). Yield: 0.908 g (88%)

(5-3) Isopropyl (Z) -9- (1R)-[(2R, 3R, 5S) -3, 5-dihydroxy-2-(-3-oxodecyl) cyclopentyl] -7-one Manufacture of noate 76

Compound 75 (0.305 g) was dissolved in a mixed solvent (6 mL) consisting of acetic acid, THF and water (2: 1: 1) and held at 50 ° C. for 14 hours. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (76). Yield: 0.213 g (90%)

[Compound (76) [Q ₁ '= Q ₂ ' = H, Rb '-Rc' = hexyl, P ₃ = isopropyl]

NMR (CDCl ₃ ) : 0.85 (t, 3H, J = 6.5Hz), 1.20 (d, 6H, J-6Hz), 1.23-2.65 (m, 34H), 3.86 (m, 1H), 4.16 (m, 1H), 4.99 (Hept , 1H, J = 6Hz), 5.39 (m, 2H)

[Manufacture example 6]

20-ethyl- ₂ -decarboxy-2- (2-carboxyethyl-13, 14-dihydro-15-keto-PGF ₂ isopropyl ester (46) [IUPAC nomenclature: isopropyl (Z) -9- (1R )-[(2R, 3R) -3-hydroxy-5-oxo-2- (3-oxodecyl) cyclopentyl] -7-nonenoate]

(6-1) (Z) -9- (1R)-[(2R, 3R) -2- (3, 3-ethylenedioxydecyl) -5-oxo-3- (tetrahydropyranyloxy) cyclopentyl ] -7-Nenonoate (77) Preparation

Oxalyl chloride (2M, 0.45 mL) and DMSO (0.13 mL) are added to dichloromethane (5 mL) previously cooled to -70 ° C and the resulting mixture is stirred for 15 h. Isopropyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- (3, 3-ethylenedioxydecyl) -5-hydroxy- (3-tetra in dichloromethane (7 mL) A solution of hydropyranyloxy) cyclopentyl] -7-nonenoate 75 (0.35 g) is added dropwise to the solution. After stirring at −55 ° C. for 15 minutes, the resulting mixture is treated with triethylamine (0.25 mL) and warmed to 10 ° C. over 6 hours. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (77). Yield: 0.311 g (89%)

(6-2) (Z) -9- (1R)-[(2R, 3R) -3-hydroxy-5-oxo-2- (3-oxydecyl) cyclopentyl] -7-nonenoate (78 Manufacturing

Compound (77) (0.3116 g) is dissolved in a mixed solvent (5 mL) consisting of acetic acid, THF and water (2: 1: 1) and maintained at 50 ° C. for 3 hours. The resulting mixture is worked up in a conventional manner and the residue is subjected to silica gel column chromatography to give the title compound (78). Yield: 0.156 g (66%)

Compound (46) [Q ₁ '= Q ₂ ' = H, Rb '= Rc' = hexyl, P ₃ = isopropyl]

NMR (CDCl ₃ ) : 0.86 (t, 3H, J = 6.5Hz), 1.20 (d, 6H, J-6Hz), 1.23-2.75 (m, 33H), 4.20 (m, 1H), 4.99 (Hept, 1H, J = 6Hz) , 5.15-5.50 (m, 2H)

[Manufacture example 7]

2-decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-16, 16-difluoro-15-keto-PGF ₂ (79) [IUPAC Nomenclature: (Z) -9- (1R )-[(2R, 3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxopentyl] -7-nonenoic acid]

Preparation of the starting compound: (6-carboxyhexyl) triphenylphosphonium bromide (n).

A mixture of 7-bromoheptanonitrile (1) (10.0 g) and 40% hydrobromic acid (80 mL) is heated to reflux for 6 hours. The mixture is diluted with water, extracted with ether and then worked up in the usual manner to give the crude product. The residue was subjected to silica gel column chromatography to give 7-bromoheptanoic acid (n). Yield: 7.60 g (69%)

Treatment of 7-bromoheptanoic acid (n) (7.60 g) with triphenylphosphine (10.0 g) affords (6-carboxyhexyl) -triphenylphosphonium bromide (n). Yield: 16.0 g (93%)

Preparation of the desired compound

(7-1) (1S, 5R, 6R, 7R) -6- (4, 4-difluoro-3-oxooctenyl) -7-tetrahydropyranyloxy) -2-oxabicyclo [3. 3. Preparation of 0] -octane-3-one (82)

(1S, 5R, 6R, 7R) -6- (5-commercially available using oxalyl chloride (2.0 M, 109.3 mL), DMSO (31.0 mL) and trimethylamine (150 mL) in dichloromethane (800 mL). Butyldimethylsilyloxymethyl) -7- (tetrahydropyranyloxy) -2-oxabicyclo [3. 3. (1S, 5R, 6R, 7R) -6-hydroxymethyl-7- (tetrahydropyranyloxy) -2-oxabicyclo [3] obtained from 0] -octan-3-one (79). . 3. 0] octan-3-one (48) (27.8 g) is swern oxidized to yield compound 81 (P ₁ = tetrahydropyranyl).

The compound (81) is reacted with dimethyl 3, 3-difluoro-2-oxoheptylphosphonate (30.0 g) in dichloromethane in the presence of thallium methoxide (8.23 mL). The resulting mixture was worked up in a conventional manner and the crude product obtained was subjected to silica gel column chromatography to give the title compound 82. Yield: 24.4 g (58%).

(7-2) (1S, 5R, 6R, 7R) -6- (4, 4-difluoro-3-oxooctyl) -7-tetrahydropyranyloxy-2-oxabicyclo [3. 3. 0] Preparation of Octane-3-one (83)

Compound 82 (12.7 g) was catalytically hydrogenated on 5% palladium on carbon (catalyst amount) in ethyl acetate (300 mL) under a hydrogen atmosphere to afford the title compound 83. Yield: 12.5 g (99%)

(7-3) (1S, 5R, 6R, 7R) -6- [4, 4-difluoro-3 (R, S) -hydroxyoctyl] -7-tetrahydroxypyranyloxy) -2- Oxabicyclo [3. 3. 0] Preparation of Octane-3-one (84)

Compound 83 (12.6 g) is obtained as title compound 84 as sodium borohydride (1.25 g) in methanol (400 mL) at 0 ° C. Yield: 12.1 g (95.5%)

(7-4) (1S, 5R, 6R, 7R) -6- [4, 4-difluoro-3 (R, S) -hydroxyoctyl] -7-tetrahydroxypyranyloxy) -2- Oxabicyclo [3. 3. 0] Preparation of Octane-3 (R, S) -ol (85)

Compound 84 (12.1 g) was reduced to diisobutylaluminum hydride (1.5M, 65.1 mL) in toluene (500 mL) at -78 ° C, and the crude product obtained was subjected to elution gel column chromatography. 85) is obtained. Yield: 11.1 g (91%)

(7-5) penacyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- {4, 4-difluoro-3 (RS) -hydroxyoctyl} -5-hydr Preparation of Roxy-3- (tetrahydrocypyranyloxy) cyclopentyl] -7-nonenoate (87)

Sodium hydride (60%, 1.63 g) is washed with pentane. DMSO (40 mL) was added thereto and the resulting mixture was maintained at 65 to 70 ° C. for 1.5 hours. After cooling to room temperature, carboxyhexylphosphonium bromide (n) (9.61 g) is added to the mixture to form an illide. A solution of compound (85) in DMSO (15 mL) is added dropwise to the illi in the solution and the mixture is kept at room temperature overnight. The resulting mixture is worked up in a conventional manner to give compound (86). Yield: 3.18 g (not purified)

Compound (86) (0.795 g), phenacyl bromide (1.01 g) and diisopropylethylamine (0.89 mL) were dissolved in acetonitrile (10 mL) and the solution was allowed to stand at room temperature for 20 minutes, then at 30 ° C. Hold for minutes. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (87). Yield: 0.604 g

(7-6) Penacyl (Z) -9- (1R)-[(2R, 3R) -2- {4, 4-difluoro-3-oxooctyl} -5-oxo-3- (tetrahydro Preparation of Cypyranyloxy) -cyclopentyl] -7-nonenoate 88

DMSO (0.92 mL) is added dropwise to a solution of oxalyl chloride (0.52 mL) (cooled to −78 ° C.) in dichloromethane (30 mL). Compound (87) (0.609 g) dissolved in dichloromethane (15 mL) is added to the solution and the resulting mixture is stirred at −30 ° C. to 20 ° C. for 1.5 h. The resulting mixture is treated with triethylamine (1.88 mL) and stirred for 30 minutes. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (88). Yield: 0.514 g (85%)

(7-7) penacyl (Z) -9- (1R)-[(2R, 3R) -2- {4, 4-difluoro-3-oxooctyl} -3-hydroxy-5-oxocyclo Preparation of Pentyl] -7-nonenoate 78

Compound 88 (0.514 g) is dissolved in a mixed solvent (30 mL) consisting of acetic acid, THF and water (4: 2: 1) and the solution is kept at room temperature overnight. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (78). Yield: 0.272 g (61%)

Compound (78) [Q ₁ '= Q ₂ ' = F, Rb '= Rc' = butyl, P ₃ = phenacyl]

NMR (CDCl ₃ ) : 0.92 (t, 3H, J = 7.5 Hz), 1.2-2.9 (m, 27H), 4.18 (m, 1H), 5.4 (m, 2H), 7.4-8.0 (m, 5H)

(7-8) (Z) -9- (1R)-[(2R, 3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] Preparation of -7-Nenoic Acid (89)

A solution of compound 78 (0.272 g) in acetic acid (10 mL) was treated with zinc (3.5 g) with the addition of small portions at room temperature for 2.5 hours. The resulting mixture is worked up in a conventional manner and the residue is subjected to silica gel column chromatography to give the title compound (89). Yield: 0.177 g (81%)

Compound (89) [Q ₁ '= Q ₂ ' = F, Rb '-Rc' = Butyl]

NMR (CDCl ₃ ) : 0.93 (t, 3H, J = 6.5 Hz), 1.15-2.95 (m, 28H), 4.19 (m, 1H), 5.36 (m, 1H)

[Manufacture example 8]

2-decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-16, 16-difluoro-15-keto-PGE ₁ isopropyl ester [IUPAC naming: isopropyl-9- (1R) Preparation of [[(2R, 3R) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] nonanoate]

(8-1) isopropyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- {4, 4-difluoro- (3RS) -hydroxyoctyl} -5-hydroxy Preparation of 3- (tetrahydropyranyloxy) cyclopentyl] -7-nonenoate (87)

Compound 86 (0.802 g), DBU (0.76 mL) and isopropyl iodide (0.51 mL) obtained in Preparation Example 5 were dissolved in acetonitrile (15 mL) and maintained at 50 ° C. for 1 hour. Another compound (86) (1.492 g) is treated in the same manner. The resulting mixture is worked up in a conventional manner to afford the title compound 87. Yield (sum): 0.315g

(8-2) isopropyl 9- (1R)-[(2R, 3R) -2- {4, 4-difluoro- (3RS) -hydroxyoctyl} -5-hydroxy-3- (tetrahydro Preparation of pyranyloxy) cyclopentyl] -7-nonenoate 90

Compound 87 (0.315 g) was catalytically hydrogenated on palladium on carbon (5%, 0.08 g) in ethanol (20 mL) under hydrogen atmosphere to afford the title compound 90. Yield: 0.301 g (95%)

(8-3) isopropyl 9- (1R)-[(2R, 3R) -2- {4, 4-difluoro-3-oxooctyl} -5-oxo-3- (tetrahydropyranyloxy) -Cyclopentyl] nonenoate (91)

Compound 90 (0.301 g) is swern oxidized with oxalyl chloride (0.34 mL), DMSO (0.61 mL) and triethylamine (1.22 mL) in dichloromethane to afford the title compound (91). Yield: 0.288 g (96%)

(8-4) isopropyl 9- (1R)-[(2R, 3R) -2- {4, 4-difluoro-3-oxooctyl} -3-hydroxy-5-oxycyclopentyl-noneno Preparation of Eight 92

Compound 91 (0.288 g) is dissolved in a mixed solvent (30 mL) consisting of acetic acid, water and THF (4: 2: 1) and the solution is held at 45 ° C. for 3.5 hours. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (92). Yield: 0.184 g (76%)

Compound (92) [Q ₁ '= Q ₂ ' = F, Rb '-Rc' = butyl, P ₃ = isopropyl]

NMR (CDCl ₃ ) : 0.94 (t, 3H, J = 6.5 Hz), 1.24 (d, 6H, J = 6 Hz), 1.27-2.95 (m, 31H), 4.19 (m, 1H), 5.02 (seven line, 1H, J = 6 Hz )

Compounds of formula (1) wherein D is -CO-CH ₂ -and compounds of formula (1) wherein D is -C≡C- can be prepared as follows.

[Manufacture example 9]

Preparation of 2-decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-6, 15-diketo-PGF ₁ isopropyl ester

Compound 75 obtained in Preparation Example 3 was dissolved in a mixture of anhydrous tetrahydrofuran and anhydrous methylene chloride. Slight excess of N-bromosuccinimide is added to the solution at 0 ° C. and the resulting mixture is stirred for 5 minutes. The resulting mixture was worked up in a conventional manner and the crude product was column chromatographed to give compound (93) (Q ₁ '= Q ₂ ' = H, Rb '-Rc' = butyl, P ₁ = tetrahydroxypyranyl , P ₂ = ethylene, P ₃ = isopropyl). It is dissolved in anhydrous toluene. The solution is treated with DPU and stirred at 40 ° C. overnight. After cooling with ice, the solution is acidified with N-HCl, stirred for 10 minutes and extracted with ethyl acetate. The resulting mixture is worked up in a conventional manner and the residue is column chromatographed to give compound 94 (sign has the same meaning as above). The protective group is removed in the same manner as in Step (3-3) of Preparation Example 3 to obtain the title compound.

[Production Example 10]

Preparation of ₂ -decarboxy-2- (2-carboxyethyl) -5, 6-dihydro-13, 14-dihydro-15-keto-PGE ₂ methyl ester

t-butyl lithium was added to a solution of 8-methoxy-3, 3-ethylenedioxy-1-iodooctane (prepared according to JP-A-52753 / 1989) in ether over 30 minutes at -78 ° C. Add dropwise and stir the resulting mixture for 3 hours. Then, a solution of copper iodide and tributylphosphine in ether, cooled to −78 ° C., is added to the mixture in one portion, and the resulting mixture is stirred for 20 minutes to form complex (j). A solution of 4R-t-butyldimethylsilyloxy-2-cyclopenten-l-one (95) in tetrahydrofuran is added dropwise to the mixture over 95 minutes. The resulting mixture is stirred for 15 minutes and transferred to a cooling bath at -30 ° C. A solution of 8-methoxycarbonyl-1-ioctine (k) in HAPA is added to the cooled mixture and then stirred for 4.5 hours. After stirring for 12 hours at room temperature, the mixture is poured into aqueous ammonium chloride. The organic layer is separated and worked up in the usual manner to give the crude product. The crude product is column chromatographed to give compound 96 [Q ₁ '= Q ₂ ' = H, Rb '-Rc' = butyl, P ₃ = methyl, P ₅ = t-butyldimethylsilyl]. Deprotection of compound (96) in conventional manner affords the title compound.

[Production Example 11]

20-Decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-16, 16-difluoro-15-keto-PGF ₂ methyl ester (72) [IUPAC nomenclature: methyl (Z) -9 Preparation of-(1R)-[(2R, 3R, 5S) -2- (4, 4-difluoro-3-oxooctyl) -3, 5-dihydroxycyclopentyl] -7-nonenoate]

(11-1) (1S, 5R, 6R, 7R) -6- [3 (R, S) -t-butyldimethylsilyloxy-4, 4-difluorooctyl] -7- (tetrahydropyranyloxy ) -2-oxabicyclo [3. 3. 0] Preparation of Octane-3 (R, S) -ol (98)

Compound (84) [Q ₁ '= Q ₂ ' = F, P ₁ = tetrahydropyranyl, Rb'-Rc '= butyl] (1.26 g) to imidazole (2.63 g) and t in DMF (15 mL) Treatment with butyldimethylsilyl chloride (2.91 g) affords silyl ether (97), yield: 1.43 g (88%).

Reduction of silyl ether (97) (1.43 g) with diisobutyl aluminum hydride in a conventional manner affords the title compound (98).

Yield: 1.47 g (100%)

(11-2) Methyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- {3 (R, S) -t-butyldimethylsilyloxy-4, 4-difluorooctyl } -5-hydroxy-3- (tetrahydrocypyranyloxy) cyclopentyl] -7-nonenoate (100)

Ilide is prepared from sodium hydride (60%, 0.934 g), DMSO (25 mL) and (6-carboxyhexyl) triphenylphosphonium bromide (5.50 g) in a conventional manner. Ilide is added to a solution of compound 98 in ether (8 mL) and the resulting mixture is stirred at room temperature for 2 hours. The resulting mixture is kept at 45 ° C. for 1 hour and then at 60 ° C. overnight. The resulting mixture is worked up in a conventional manner to give carboxylic acid 99, which is treated with diazomethane. The product is subjected to silica gel column chromatography to give the title compound (100). Yield: 0.43 g (48%)

(11-3) Methyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- {3 (R, S) -t-butyldimethylsilyloxy-4, 4-difluorooctyl } -3, 5- (ditetrahydropyranyloxy) cyclopentyl] -7-nonenoate (101)

Compound 100 (0.438 g) is converted to ditetrahydropyranyl ether using an excess amount of dihydropyran and a catalytic amount of p-toluenesulfonic acid in dichloromethane (25 mL). The resulting mixture is subjected to silica gel column chromatography to give compound (101). Yield: 0.494 g (99%)

(11-4) Methyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- (t-butyldimethylsilyloxy-3-oxooctyl) -3, 5- (ditetrahydrocy Preparation of pyranyloxy) cyclopentyl] -7-nonenoate (103)

Compound 101 (0.94 g) is dissolved in THF (10 mL). Tetrabutylammonium trifluoride (1.0 M, 5.6 mL) is added to the solution and the resulting mixture is allowed to stand overnight. The resulting mixture is then worked up in a conventional manner to afford deprotected compound 102. Yield: 0.284 g (68%)

Compound 102 (0.284 g) is sworn oxidized using oxalyl chloride (0.165 mL) and DMSO (0.3 mL) in dichloromethane (10 mL). The product is subjected to silica gel column chromatography to give compound (103). Yield: 0.251 g (89%)

(11-5) Methyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- (4, 4-difluoro-3-oxooctyl) -3, 5- (dihydroxy Preparation of Cyclopentyl] -7-Nenonoate 104

Compound 103 is dissolved in a mixed solvent (30 mL) consisting of acetic acid and THF (4: 2: 1) and the solution is maintained at 45-50 ° C. for 3 hours. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound 104. Yield: 0.137 (76%)

Compound (72) [Q ₁ '= Q ₂ ' = F, Rb '-Rc' = butyl, P ₃ = methyl]

NMR (CDCl ₃ ) : 0.92 (t, 3H, J = 7.5 Hz), 1.2-2.9 (m, 38H) 3.67 (s, 3H), 3.70 (q, 1H, J = 7.5 Hz), 4.25 (m, 1H), 5.43 (m , 2H)

[Manufacture example 12]

2-decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-16, 16-difluoro-15-keto-PGE ₁ (105) [IUPAC Nomenclature: (Z) -9- (1R )-[(2R, 3R, 5S) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxocyclopentyl] nonanoic acid]

(12-1) benzyl (Z) -9- (1R)-[(2R, 3R, 5S) -3- {4, 4-difluorooctyl} -3 (R, S) -hydroxyoctyl}- Preparation of 5-hydroxy-3- (tetrahydropyranyloxy) cyclopentyl] -7-nonenoate (87)

Compound (54) [Q ₁ '= Q ₂ ' = F, P ₁ = tetrahydropyranyl, Rb'-Rc '= butyl] (1.09 g) was dissolved in acetonitrile (20 mL) and DBU (2.6 mL) ) And benzyl bromide (2.2 mL) are added to the solution. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (87). Yield: 0.213 g

(12-2) benzyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- {4, 4-difluorooctyl} -3-oxooctyl-3-tetrahydropyranyloxy ) -5-oxocyclopentyl] -7-nonenoate (88)

Compound 87 (0.21 g) is swern oxidized using oxalyl chloride (0.23 mL), DMSO (0.41 mL) and triethylamine (0.81 mL) in dichloromethane (15 mL). The product is subjected to silica gel column chromatography to give the title compound (88). Yield: 0.181 g (86%)

(12-3) benzyl (Z) -9- (1R)-[(2R, 3R, 5S) -2- (4, 4-difluoro-3-oxooctyl) -3-hydroxy-5-oxo Preparation of Cyclopentyl] -7-Nenonoate 78

Compound 88 (0.181 g) is dissolved in a mixed solvent (25 mL) consisting of acetic acid, water and THF (4: 2: 1) and the solution is maintained at 45 ° C. for 3.5 hours. The resulting mixture is worked up in a conventional manner and the crude product obtained is subjected to silica gel column chromatography to give the title compound (78). Yield: 0.140 (91%)

Compound (78) [Q ₁ '= Q ₂ ' = F, Rb '-Rc' = butyl, P ₃ = benzyl]

NMR (CDCl ₃ ) : 0.93 (t, 3H, J = 7.5Hz), 1.2-2.8 (m, 27H) 4.20 (m, 1H), 5.12 (s, 2H), 5.12 (s, 2H), 5.2-5.5 (m, 2H) , 7.35 (m, 5 H)

(12-4) 9- (1R)-[(2R, 3R, 5S) -2- (4, 4-difluoro-3-oxooctyl-3-hydroxy-5-oxocyclopentyl] nonanoic acid ( Manufacture of 105)

Compound 78 is dissolved in ethyl acetate (15 mL). Palladium on carbon (ml) is added to the solution and shaken under hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate is concentrated and the resulting crude product is subjected to Lobar column (ODS) chromatography to afford the title compound 105. Yield: 0.077 g (65%)

Compound (105) [Q ₁ '= Q ₂ ' = F, Rb '-Rc' = Butyl]

NMR (CDCl ₃ ) : 0.95 (t, 3H, J = 7.5 Hz), 1.2-2.8 (m, 32H) 4.20 (m, 1H)

[Production Example 13]

20-ethyl-2-decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-16, 16-difluoro-15-keto-PGE ₁ isopropyl ester (92) [IUPAC naming: iso Of propyl (Z) -9- (1R)-[(2R, 3R) -2- (4, 4-difluoro-3-oxodecyl) -3-hydroxy-5-oxocyclopentyl] nonanoic acid] Produce

Except for using dimethyl (3, 3-difluoro-2-oxononyl) phosphonate, the process of Preparation Example 6 is repeated to afford the title compound 60.

Compound (60) [Q ₁ '= Q ₂ ' = F, Rb '-Rc' = hexyl, P ₃ = isopropyl]

NMR (CDCl ₃ ) : 0.93 (t, 3H, J = 7.5 Hz), 1.32 (d, 6H, J = 6 Hz), 1.25-2.70 (m, 34H) 3.15 (s, 1H), 4.20 (m, 1H), 5.00 (seven lines) , 1H, J = 7.5Hz)

Production Example 14

2-Decarboxy-2- (2-carboxyethyl) -13, 14-dihydro-15-keto-PGE ₁ isopropyl ester (78) [IUPAC nomenclature: isopropyl (Z) -9- (1R)-[ Preparation of (2R, 3R) -2- (3-oxopentyl) -3-hydroxy-5-oxocyclopentyl] -7-nonenoate]

Except for using dimethyl 2-oxoheptylphosphate, the process of Preparation Example 4 is repeated to afford the title compound 78.

Compound (78) [Q ₁ '= Q ₂ ' = H, Rb '-Rc' = butyl, P ₃ = isopropyl]

NMR (CDCl ₃ ) : 0.89 (t, 3H, J = 6.6 Hz), 1.18 (d, 6H, J = 6.2 Hz), 1.15-3.0 (m, 29H) 4.04 (ms, 1H), 4.99 (seven line, 1H, J = 6.2 Hz), 5.37 (m, 2H)

[Example 1]

(Injection powder)

(Parts by weight)

13, 14-dihydro-15-keto-16, 16-difluoro-PGE ₂ 1

Mannitol 5

Distilled water 0.4

The ingredients are mixed, stirred, sterilized, filtered and lyophilized to give an injectable powder.

[Example 2]

(Injection amount) (part by weight)

13, 14-dihydro-15-keto-16, 16-difluoro-PGE ₂ 0.2

Nonionic Surfactants 2

Distilled Water 98

The components are mixed and sterilized to obtain an injection solution.

[Example 3]

13, 14-dihydro-15-keto-16, 16-difluoro-20-methyl-PGE ₂ (50 mg) dissolved in methanol (10 mL) is mixed with mannitol (18.5 g). The mixture is sorted (with a sieve having a pore size of 30 mm in diameter), dried and sorted again. The powder obtained as described above was mixed with finely divided silica gel (Aerosil ^* , 200 g) and filled into hard gelatine capsule 100 three times, 0.5 mg of 13, 14-dihydro-15-keto-16 per capsule. A capsule for enteral administration containing 16-difluoro-20-ethyl-PGE ₂ is obtained.

* product name

[Example 4]

(Oral powder)

(Parts by weight)

13, 14-dihydro-15-keto-16, 16-difluoro-PGE ₁ 5

Methyl ester

Weak silicic anhydride 5

Avicel ^* 20

Lactose 70

The above ingredients are mixed to obtain a powder for oral administration.

* product name

[Example 5]

(Soft Gelatin Capsules)

(Parts by weight)

13, 14-dihydro-6, 15-diketo-5, 5-difluoro-PGE ₁ 1

Methyl ester

Weak Silic Anhydride 899

Panasate ^* 20

The ingredients are mixed and filled into soft gelatin capsules.

* product name

[Example 6]

(Capsule for enteral administration)

16-Desbutyl-13, 14-dihydro-15-keto-16- (m-trifluoromethyl) phenoxy-PGF _2α (50 mg) dissolved in methanol (10 mL) was mixed with mannitol (18.5 g). Let's do it. The mixture is sorted (using a sieve having a pore size of 30 mm in diameter), dried at 30 ° C. for 90 minutes and then sorted again. The powder thus obtained was mixed with finely divided silica gel (aerosil ^* , 200 g) and filled into hard gelatine capsule 100 three times, and 0.5 mg of 13, 14-dihydro-15-keto-16-desbutyl per capsule A capsule for enteral administration containing -16-m-trifluoromethylphenoxy-PGF _2α is obtained.

* Trade Name

[Example 7]

(Injection powder)

(Parts by weight)

13, 14-dihydro-15-keto-16-desbutyl-

16-m-trifluoromethylphenoxy-PGF ₂ 1

Mannitol 5

Distilled water 0.4

The components are mixed and sterilized to obtain an injection solution.

[Example 8]

(Injection amount)

(Parts by weight)

13, 14-dihydro-6, 15-diketo-5R, S-fluoro-PGE ₁ 0.2

Nonionic Surfactants 2

Distilled Water 98

The components are mixed and sterilized to obtain an injection solution.

[Example 9]

(Oral powder)

(Parts by weight)

13,14-dihydro-15-keto-16-desbutyl-16-m-

Trifluoromethylphenoxy-PGF ₂ 5

Weak silicic anhydride 5

Avicel ^* 20

Lactose 70

The above ingredients are mixed to obtain a powder for oral administration.

* product name

[Example 10]

(Soft Gelatin Capsules)

(Parts by weight)

13,14-dihydro-15-keto-16-desbutyl-16-m-

Trifluoromethylphenoxy-PGE ₂ 1

Weak Silic Anhydride 899

Panaceate ^* 20

The ingredients are mixed and filled into soft gelatin capsules.

* product name

[Example 11]

(eye drops)

13, 14-dihydro-15-keto-20-ethyl-PGF _2α 10 mg

Isopropyl ester

10 ml of saline solution

The components are placed in separate vials, combined and mixed at the time of use to prepare eye drops.

In the above formulations, the components may be replaced with any other compound in the compounds used in the present invention.

[Test Example 1]

(Way)

Japanese white rabbit males (weight: 2.5 to 3.2 kg) are used as test animals. Using a 5.5 mm diameter perforator, make a circular wound on the surface of the central portion of the left eye cornea and remove the outer cornea in the circle by rubbing with the tip of a cotton swab dipped in sterile saline solution. To determine the recovery of the exfoliated portion, the fluorescein-stainable area is examined and the time elapsed until the stainable area disappears. The test compound was dissolved in physiological saline and administered to the eye treated as above, 5 days at an interval of 1 hour and thereafter, externally administered 5 times daily at 2 hours until there is no dyeable area. 35 μl / eye). Only control saline is administered to the control eye.

(result)

The results are shown in the table below.

Test compound 1: 13, 14-dihydro-15-keto-20-ethyl-PGF isopropyl ester.

[Test Example 2]

(Way)

Six Japanese white rabbit males (weight: 2.5 to 3.2 kg) are used as test animals in a group of six. Using a perforator with a diameter of 5.5 mm, a circular wound is made on the surface of the central portion of the cornea of the left eye, and the outer cornea of the inner circle is removed by rubbing with the tip of a cotton swab dipped in sterile saline solution. To determine the recovery of the exfoliated portion, the fluorescein-stainable area is examined and the time elapsed until the stainable area disappears. The test compound is dissolved in physiological saline and administered externally (35 μl / eye) five times daily at an hourly interval and thereafter at five hourly daily intervals on the same day of treatment to the eyes treated as above. Fluorescein-stainable areas (%, taking 100% dyeable areas immediately after treatment) are recorded at 6, 24 and 30 hours after treatment. Only control saline is administered to the control eye.

(result)

The results are shown in the table below.

Test Compound 2: 13, 14-dihydro-15-keto-16, 16-difluoro-PGE.

From the above results, it can be clearly seen that the test compound has the activity of improving wound-treatment in the experimental corneal wound model.

[Test Example 3]

(Way)

Wistar rat males (7 weeks old, weight: 240-280 g) are used as test animals. An incision is made in the back skin of the rat that is about 3cm long and extends to the dermis. Immediately afterwards, three stitches are wound on the wound at equal intervals with a thread (hard, number 3). The test compound (about 0.3 g / wound) is applied to the wound once immediately after treatment and twice daily (morning and evening) for 5 days. On day 4, the thread is removed, and on day 6 the tensile strength TS is measured. Tensile strength is measured as follows. A rectangular piece of back skin is cut into the wound at a length of 1 cm. One end of the piece is fixed between the plates and the opposite end is hanged. A thread having a plastic container capable of supplying water to the pump is connected to the drooped end with a weight. Tensile strength is defined as the weight when the wound is fully open. The test compound is homogeneously dissolved at a rate of 8 μg / g in a jelly medicine having the following composition.

Propylene Glycon 2.0g

Carboxymethyl Cellulose Sodium Salt 2.0g

Sterilized water 96.0 g

Control animals are administered with only jelly medication.

Tensile strength for untreated animals is also measured as a reference value.

(result)

The results are shown in the table below.

[Test Example 4]

(Way)

The method of Example 3 is substantially repeated except hydrocortisone (5 mg / kg) is administered intramuscularly to rats once daily for 5 days from the day of treatment to delay spontaneous treatment of the wound.

(result)

Test compound 3: 13, 14-dihydro-16, 16-difluoro-15-keto-PGEisopropyl ester.

Test compound 4: 13, 14-dihydro-16, 16-difluoro-15-keto-PGE

From the above results, it can be clearly seen that the test compound has the activity of improving wound-treatment in the experimental incision wound model.

In the data below, NMR spectra were measured in CDCl using HITACHI R-90H, and mass spectra were measured by EI method at an ionization potential of 70 eV using HITACHI M-80B.

* 13, 14-dihydro-15-keto-16, 16-difluoro-PGE

H NMR (CDCl)0.93 (t, 3H, J = 7.5 Hz), 1.20-2.70 (m, 2H), 4.20 (m, 1H), 5.40 (m, 2H)

MS (DI-EI) m / z 388 (M ⁺ ), 370 (M ⁺ -H ₂ O), 352 (M ⁺ -2H ₂ O)

* 13, 14-dihydro-15-keto-16, 16-difluoro-PGE ₁ isopropyl ester

¹ H NMR (CDCl ₃ ) 0.93 (t, 3H, J = 7.5 Hz), 1.23 (d, J = 7.5 Hz), 1.20-2.70 (m, 26H), 3.15 (s, 1H), 4.18 (m, 1H), 5.00 (ht, 1H , J = 7.5 Hz)

MS (DI-EI) m / z 432 (M ⁺ ), 414 (M ⁺ -H ₂ O)

* 13, 14-dihydro-15-keto-16, 16-difluoro-PGE ₂ isopropyl ester

¹ H NMR (CDCl ₃ ) 0.93 (t, 3H, J = 7.5 Hz), 1.23 (d, 6H = 7.5 Hz),

1.30-2.70 (m, 22H), 2.78 (m, 1H), 4.20 (m, 1H), 5.00 (ht, 1H, J = 7.5 Hz) MS (DI-EI) m / z 430 (M ⁺ ), 412 (M ⁺ -H ₂ O)

13, 14-dihydro-15-keto-16, 16-difluoro-19-desmethyl-PGE ₂ methyl ester

¹ H NMR (CDCl ₃ ) 0.98 (t, 3H, J = 7.5 Hz), 1.50-2.70 (m, 20H), 2.94 (s, 1H), 3.68 (s, 3H), 4.20 (m, 1H), 5.40 (m, 2H)

MS (DI-EI) m / z 388 (M ⁺ ), 370 (M ⁺ -H ₂ O), 357 (M ⁺ -H ₂ OCH ₃ O), 355 (M ⁺ -H ₂ OCH ₃ )

* 13, 14-dihydro-15-keto-16, 16-difluoro-19-desmethyl-PGE ₂

¹ H NMR (CDCl ₃ ) 0.98 (t, 3H, J = 7.5 Hz), 1.40-2.70 (m, 22H), 4.20 (m, 1H), 5.40 (m, 2H)

MS (DI-EI) m / z 374 (M ⁺ ), 356 (M ⁺ -H ₂ O), 388 (M ⁺ -2H ₂ O)

13, 14-dihydro-15-keto-16, 16-difluoro-11-dehydroxy-11-methyl-PGE ₂ methyl ester

¹ H NMR (CDCl ₃ ) 0.93 (t, 3H, J = 7.5 Hz), 1.14 (d, 3H, J = 6 Hz), 1.25-2.80 (m, 22H), 3.63 (s, 3H), 5.38 (m, 2H)

MS (DI-EI) m / z 400 (M ⁺ ), 369 (M ⁺ -CH ₃ O)

13, 14-dihydro-15-keto-16, 16-difluoro-PGE ₂ methyl ester

¹ H NMR (CDCl ₃ ) 0.91 (t, 3H, J = 7.5 Hz), 1.20-3.20 (m, 23H), 3.68 (s, 3H), 4.44 (m, 1H, J = 1.2 Hz), 5.49 (m, 2H)

MS (DI-EI) m / z 402 (M ⁺ ), 384 (M ⁺ -H ₂ O), 353 (M ⁺ -H ₂ OCH ₃ O)

* 13, 14-dihydro-15-keto-16, 16-difluoro-20-methyl-PGE ₂

¹ H NMR (CDCl ₃ ) 0.90 (t, 3H, J = 7.5 Hz), 1.20-2.70 (m, 26H), 4.20 (m, 1H), 5.41 (m, 2H)

MS (DI-EI) m / z 402 (M ⁺ ), 384 (M ⁺ -H ₂ O), 366 (M ⁺ -H ₂ O)

13, 14-dihydro-15-keto-16, 16-difluoro-20-ethyl-PGE ₂ methyl ester

¹ H NMR (CDCl ₃ ) 0.89 (t, 3H, J = 7.5 Hz), 1.20-2.70 (m, 26H), 2.93 (s, 1H), 3.68 (s. 3H), 4.20 (m, 1H), 5.41 (m, 2H)

MS (DI-EI) m / z 403 (M ⁺ ), 412 (M ⁺ -H ₂ O), 399 (M ⁺ -CH ₃ O), 381 (M ⁺ -H ₂ O-CH ₃ O)

13, 14-dihydro-15-keto-16, 16-difluoro-20-ethyl-PGE ₂

¹ H NMR (CDCl ₃ ) 0.94 (t, 3H, J = 7.5 Hz), 1.20-2.70 (m, 27H), 4.21 (m, 1H), 5.43 (m, 2H)

MS (DI-EI) m / z 416 (M ⁺ ), 398 (M ⁺ -H ₂ O), 380 (M ⁺ -2H ₂ O)

Claims (12)

A composition for promoting the treatment of a wound, comprising a 13, 14-dihydro-15-keto-prostaglandin E or F compound with a pharmaceutically acceptable carrier, diluent or excipient. The composition of claim 1 wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-16-mono- or di-halo-15-keto-prostaglandin E or F compound . The compound of claim 1, wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-16-mono- or di-fluoro-15-keto-prostaglandin E or F compound. Composition. The composition of claim 1, wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-16, 16-difluoro-15-keto-prostaglandin E or F compound. The composition of claim 1 wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-15-keto-20-alkyl-prostaglandin E or F compound. The composition of claim 1, wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-15-keto-20-ethyl-prostaglandin E or F compound. A pharmaceutical composition for promoting the treatment of a wound of a cornea comprising a 13, 14-dihydro-15-keto-prostaglandin E or F compound with a pharmaceutically acceptable carrier, diluent or excipient. The composition of claim 7 wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-16-mono- or di-halo-15-keto-prostaglandin E or F compound. . The compound of claim 7, wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-16-mono- or di-fluoro-15-keto-prostaglandin E or F compound. Composition. 8. The composition of claim 7, wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-16, 16-difluoro-15-keto-prostaglandin E or F compound. 8. The composition of claim 7, wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-15-keto-20-alkyl-prostaglandin E or F compound. 8. The composition of claim 7, wherein the 13, 14-dihydro-15-keto-prostaglandin E or F compound is a 13, 14-dihydro-15-keto-20-ethyl-prostaglandin E or F compound.